Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors

ABSTRACT

A pharmaceutical composition comprises a solid amorphous dispersion of a cholesteryl ester transfer protein inhibitor and a concentration-enhancing polymer.

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/918,127, filed Jul. 3, 2001, which claims the benefit ofpriority of U.S. provisional patent application No. 60/223,279 filedAug. 3, 2000.

BACKGROUND OF THE INVENTION

This invention relates to cholesteryl ester transfer protein (CETP)inhibitors, pharmaceutical compositions containing such inhibitors andthe use of such inhibitors to elevate certain plasma lipid levels,including high density lipoprotein (HDL)-cholesterol and to lowercertain other plasma lipid levels, such as low density lipoprotein(LDL)-cholesterol and triglycerides and accordingly to treat diseaseswhich are affected by low levels of HDL cholesterol and/or high levelsof LDL-cholesterol and triglycerides, such as atherosclerosis andcardiovascular diseases in certain mammals (i.e., those which have CETPin their plasma), including humans.

CETP inhibitors, particularly those that have high binding activity, aregenerally hydrophobic, have extremely low aqueous solubility and havelow oral bioavailability when dosed conventionally. Such compounds havegenerally proven to be difficult to formulate for oral administrationsuch that high bioavailabilities are achieved.

Atherosclerosis and its associated coronary artery disease (CAD) is theleading cause of death in the industrialized world. Despite attempts tomodify secondary risk factors (smoking, obesity, lack of exercise) andtreatment of dyslipidemia with dietary modification and drug therapy,coronary heart disease (CHD) remains the most common cause of death inthe U.S., where cardiovascular disease accounts for 44% of all deaths,with 53% of these associated with atherosclerotic coronary heartdisease.

Risk for development of this condition has been shown to be stronglycorrelated with certain plasma lipid levels. While elevatedLDL-cholesterol may be the most recognized form of dyslipidemia, it isby no means the only significant lipid associated contributor to CHD.Low HDL-cholesterol is also a known risk factor for CHD (Gordon, D. J.,et al., “High-density Lipoprotein Cholesterol and CardiovascularDisease,” Circulation, (1989), 79: 8-15).

High LDL-cholesterol and triglyceride levels are positively correlated,while high levels of HDL-cholesterol are negatively correlated with therisk for developing cardiovascular diseases. Thus, dyslipidemia is not aunitary risk profile for CHD but may be comprised of one or more lipidaberrations.

Among the many factors controlling plasma levels of these diseasedependent principles, cholesteryl ester transfer protein (CETP) activityaffects all three. The role of this 70,000 dalton plasma glycoproteinfound in a number of animal species, including humans, is to transfercholesteryl ester and triglyceride between lipoprotein particles,including high density lipoproteins (HDL), low density lipoproteins(LDL), very low density lipoproteins (VLDL), and chylomicrons. The netresult of CETP activity is a lowering of HDL cholesterol and an increasein LDL cholesterol. This effect on lipoprotein profile is believed to bepro-atherogenic, especially in subjects whose lipid profile constitutesan increased risk for CHD.

No wholly satisfactory HDL-elevating therapies exist. Niacin cansignificantly increase HDL, but has serious toleration issues whichreduce compliance. Fibrates and the HMG CoA reductase inhibitors raiseHDL-cholesterol only modestly (±10-12%). As a result, there is asignificant unmet medical need for a well-tolerated agent which cansignificantly elevate plasma HDL levels, thereby reversing or slowingthe progression of atherosclerosis.

CETP inhibitors have been developed which inhibit CETP activity, andthus, if present in the blood, should result in higher HDL cholesterollevels and lower LDL cholesterol levels. To be effective, such CETPinhibitors must be absorbed into the blood. Oral dosing of CETPinhibitors is preferred because to be effective such CETP inhibitorsmust be taken on a regular basis, such as daily. Therefore, it ispreferred that patients be able to take CETP inhibitors by oral dosingrather than by injection.

However, it has proven to be difficult to formulate CETP inhibitors fororal administration such that therapeutic blood levels are achieved.CETP inhibitors in general possess a number of characteristics whichrender them poorly bioavailable when dosed orally in a conventionalmanner. CETP inhibitors tend to be quite hydrophobic and extremely waterinsoluble, with solubility in aqueous solution of usually less thanabout 10 μg/ml and typically less than 1 μg/ml. Often, the aqueoussolubility of CETP inhibitors is less than 0.1 μg/ml. Indeed, thesolubility of some CETP inhibitors is so low that it is in factdifficult to measure. Accordingly, when CETP inhibitors are dosedorally, concentrations of CETP inhibitor in the aqueous environment ofthe gastrointestinal tract tend to be extremely low, resulting in poorabsorption from the GI tract to blood. The hydrophobicity of CETPinhibitors not only leads to low equilibrium aqueous solubility but alsotends to make the drugs poorly wetting and slow to dissolve, furtherreducing their tendency to dissolve and be absorbed from thegastrointestinal tract. This combination of characteristics has resultedin the bioavailability for orally dosed conventional crystalline oramorphous forms of CETP inhibitors generally to be quite low, oftenhaving absolute bioavailabilities of less than 1%.

Various attempts have been made to improve the aqueous concentration ofCETP inhibitors, but generally have met with limited success. At theoutset, most methods aimed at enhancing aqueous concentration andbioavailability of low-solubility drugs only offer moderateimprovements. Such improvements generally lead to enhancements inaqueous concentration on the order of from one to seven fold. Inaddition, the enhancement may be short-lived, with the drugconcentration returning to the equilibrium concentration within 10 to 40minutes. Such small, short-lived concentration enhancements have led toeven lower levels of bioavailability enhancement when tested in vivo viaoral administration. Thus, when conventional dosage forms oflow-solubility drugs are tested in vivo via oral administration,bioavailability enhancements are typically on the order of 2-fold to4-fold or less. For CETP inhibitors having low absolutebioavailabilities, such small improvements are insufficient to allowconvenient oral dosing of CETP inhibitors; that is, dosage forms havinga convenient size and frequency of dosing.

Moreover, some standard methods for improving the concentration ofpharmaceuticals in aqueous solution have proven inadequate when appliedto CETP inhibitors. For example, even pre-dissolving the CETP inhibitorin a water miscible solvent such as polyethylene glycol followed bydelivery as a solution to an aqueous environment of use has failed toraise the aqueous concentration of CETP inhibitor to an acceptablelevel.

Sikorski, et al., WO 99/14204, and Lee, et al., WO 99/41237, bothdisclose CETP inhibitors formulated for oral administration usinghydroxy propyl methyl celluose in a controlled release dosage form whichis characterized as a “dispersion.” Both Sikorski and Lee appear to beusing the term “dispersion” to mean a controlled release matrix in whichdrug particles are distributed within a polymer matrix that slowlyerodes rather than a solid amorphous dispersion of the type of thepresent invention. Such controlled release matrix compositions wouldslow rather than enhance the dissolution and absorption of CETPinhibitor. In any event, both Sikorski and Lee state that CETPinhibitors may be orally dosed by simply dissolving the CETP inhibitorin water without any discussion of the difficulty of dissolving the CETPinhibitors in water. There is no recognition in either Sikorski or Leeof the need to improve the aqueous concentration or bioavailability ofCETP inhibitors.

Curatolo et al., EP 0 901 786 A2 disclose solid pharmaceuticaldispersions with enhanced bioavailability using spray dried dispersionsof a sparingly soluble drug and hydroxy propyl methyl cellulose acetatesuccinate. However, Curatolo et al. do not disclose the use of CETPinhibitors, or discuss the problems associated with the formulation ofCETP inhibitors for oral administration.

Nakamichi et al., U.S. Pat. No. 5,456,923 disclose an extrusion processfor producing solid dispersions of sparingly soluble drugs and a varietyof polymeric materials, such as hydroxy propyl methyl cellulose acetatesuccinate. However, Nakamichi et al. does not disclose dispersionscontaining CETP inhibitors, much less discuss the problems associatedwith formulating hydrophobic drugs.

Accordingly, there is still a need for developing compositions of CETPinhibitors that may be orally dosed, that improve the aqueousconcentration of such drugs, that improve the bioavailablity of suchdrugs relative to compositions of the drugs alone, and that does notadversely affect the ability of the drugs to act therapeutically.

BRIEF SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of the prior art byproviding pharmaceutical compositions comprising a solid amorphousdispersion of a CETP inhibitor and a concentration-enhancing polymer, aswell as methods for making the same.

In a first aspect, a method is provided for forming the solid amorphousdispersion by solvent processing. A solution is formed comprising a CETPinhibitor and a concentration-enhancing polymer dissolved in a commonsolvent. Solvent is then rapidly removed from the solution to form asolid amorphous dispersion of the chloresteryl ester transfer proteininhibitor and the concentration-enhancing polymer.

In another aspect of the invention, a method for forming pharmaceuticalcompositions by melt extrusion is provided. A CETP inhibitor and aconcentration-enhancing polymer are fed to an extruder. The CETPinhibitor and polymer are extruded through the extuder and then rapidlysolidified to form a solid amorphous dispersion comprising thechloresteryl ester transfer protein inhibitor and theconcentration-enhancing polymer.

In a third aspect of the invention, a method for forming pharmaceuticalcompositions by melt congealing is provided. A molten mixture comprisinga CETP inhibitor and a concentration-enhancing polymer is formed. Themixture is then cooled to form a solid amorphous dispersion comprisingthe chloresteryl ester transfer protein inhibitor and theconcentration-enhancing polymer.

In addition, several compositions are provided comprising chloresterylester transfer protein inhibitors and concentration-enhancing polymers.Several different chloresteryl ester transfer protein inhibitors areprovided, including(4′S)-5′-(4-fluorophenyl)-6′-[(S)-fluoro[4-(trifluoromethyl)phenyl]methyl]-3′,4′-dihydro-7′-(1-methylethyl)-spiro[cyclobutane-1,2′(1′H)-naphthalen]-4′-oland(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol,and pharmaceutically acceptable forms thereof. By “pharmaceuticallyacceptable forms” thereof is meant any pharmaceutically acceptablederivative or variation, including stereoisomers, stereoisomer mixtures,enantiomers, solvates, hydrates, isomorphs, polymorphs, salt forms andprodrugs.

In another aspect of the invention, several differentconcentration-enhancing polymers are disclosed. In one aspect of theinvention, the concentration-enhancing polymer in the solid amorphousdispersion is carboxymethyl ethyl cellulose. In another aspect of theinvention, the concentration-enhancing polymer is apolyoxyethylene-polyoxypropylene copolymer.

As used herein, a “use environment” can be either the in vivoenvironment of the GI tract of a mammal, particularly a human, or the invitro environment of a test solution, such as phosphate buffered saline(PBS) or Model Fasted Duodenal (MFD) solution.

The composition may be dosed in a variety of dosage forms, includingboth immediate release and controlled release dosage forms, the latterincluding both delayed and sustained release forms. The composition mayinclude blends of polymers, and may further include other excipientsthat improve the aqueous concentration of the CETP inhibitor.

The various aspects of the present invention each provide one or more ofthe following advantages. The compositions of the present inventionimprove the aqueous concentration of CETP inhibitors relative tocompositions that are free from concentration-enhancing polymer, byproviding aqueous concentration of CETP inhibitors of at least about10-fold that of control compositions that are free from theconcentration-enhancing polymer. Such solubility enhancements areunexpectedly large relative to that typically observed for dispersionsof other types of drugs. Accordingly, the compositions of the presentinvention comprising a CETP inhibitor and concentration-enhancingpolymer allow the dose of CETP inhibitor required to obtain adequateefficacy to be reduced.

In fact, compositions of the present invention often exhibitsurprisingly large enhancements for some CETP inhibitors, on the orderof 50 to 500-fold and in some cases up to a 80.000-fold improvement inconcentration relative to that of a control crystalline composition.Such large enhancements are, for some CETP inhibitors, necessary forconvenient oral administration. The compositions thus renderhydrophobic, substantially insoluble CETP inhibitors therapeuticallyeffective with a convenient dose (mass of drug) for oral administration.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions of CETP inhibitors and atleast one concentration-enhancing polymer. As discussed above in theBackground, CETP inhibitors generally have (1) extremely lowsolubilities in aqueous solution (i.e., less than about 10 μg/mL) atphysiologically relevant pH (e.g., any pH of from 1 through 8) measuredat about 22° C.; (2) a relatively hydrophobic nature; and (3) arelatively low bioavailability when orally dosed in the crystallinestate. Accordingly, CETP inhibitors require some kind of modification orformulation to enhance their solubility and thereby achieve goodbioavailability. Surprisingly, the compositions of the present inventionprovide unusually large enhancements in aqueous concentration in anenvironment of use and unusually large enhancements in bioavailabilitycompared with other conventional compositions used to formulate poorlysoluble, hydrophobic drugs. The inventors have found that, contrary toconventional wisdom, the compositions provide the greatest enhancementsfor those drugs which have been thought most difficult to formulate fororal delivery. Specifically, the inventors have found that preparingCETP inhibitors as compositions comprising a solid amorphous dispersionof a CETP inhibitor and concentration-enhancing polymer, and preferablyas a homogenous dispersion, improves the aqueous concentration of theCETP inhibitors as well as relative bioavailability. The compositions,CETP inhibitors, suitable polymers, and optional excipients arediscussed in more detail as follows.

Compositions of CETP Inhibitors and Concentration-Enhancing Polymer

The present invention finds utility with any low-solubility CETPinhibitor, or any CETP inhibitor which would benefit by improvedbioavailability or more rapid absorption. The compositions of thepresent invention comprise dispersions of a CETP inhibitor and at leastone concentration-enhancing polymer. The CETP inhibitor in its purestate may be crystalline or amorphous. Preferably, at least a majorportion of the CETP inhibitor in the composition is amorphous. By“amorphous” is meant simply that the CETP inhibitor is in anon-crystalline state. As used herein, the term “a major portion” of theCETP inhibitor means that at least 60% of the CETP inhibitor in thecomposition is in the amorphous form, rather than the crystalline form.Preferably, the CETP inhibitor in the dispersion is substantiallyamorphous. As used herein, “substantially amorphous” means that theamount of the CETP inhibitor in crystalline form does not exceed about25%. More preferably, the CETP inhibitor in the dispersion is “almostcompletely amorphous” meaning that the amount of CETP inhibitor in thecrystalline form does not exceed about 10%. Amounts of crystalline CETPinhibitor may be measured by powder X-ray diffraction, Scanning ElectronMicroscope (SEM) analysis, differential scanning calorimetry (DSC), orany other standard quantitative measurement.

The composition may contain from about 1 to about 80 wt % CETPinhibitor, depending on the dose of the CETP inhibitor and theeffectiveness of the concentration-enhancing polymer. Enhancement ofaqueous CETP inhibitor concentrations and relative bioavailability aretypically best at low CETP inhibitor levels, typically less than about25 to 40 wt %. However, due to the practical limit of the dosage formsize, higher CETP inhibitor levels are often preferred and in many casesperform well.

The amorphous CETP inhibitor can exist within the solid amorphousdispersion as a pure phase, as a solid solution of CETP inhibitorhomogeneously distributed throughout the polymer or any combination ofthese states or those states that lie intermediate between them. Thedispersion is preferably substantially homogeneous so that the amorphousCETP inhibitor is dispersed as homogeneously as possible throughout thepolymer. As used herein, “substantially homogeneous” means that thefraction of CETP inhibitor that is present in relatively pure amorphousdomains within the solid dispersion is relatively small, on the order ofless than 20%, and preferably less than 10% of the total amount of CETPinhibitor.

While the dispersion may have some CETP inhibitor-rich domains, it ispreferred that the dispersion itself have a single glass transitiontemperature (T_(g)) which demonstrates that the dispersion issubstantially homogeneous. This contrasts with a simple physical mixtureof pure amorphous CETP inhibitor particles and pure amorphous polymerparticles which generally display two distinct T_(g)s, one that of theCETP inhibitor and one that of the polymer. T_(g) as used herein is thecharacteristic temperature where a glassy material, upon gradualheating, undergoes a relatively rapid (e.g., 10 to 100 seconds) physicalchange from a glass state to a rubber state. The T_(g) of an amorphousmaterial such as a polymer, drug or dispersion can be measured byseveral techniques, including by a dynamic mechanical analyzer (DMA), adilatometer, dielectric analyzer, and by a differential scanningcalorimeter (DSC). The exact values measured by each technique can varysomewhat but usually fall within 10° to 30° C. of each other. Regardlessof the technique used, when an amorphous dispersion exhibits a singleT_(g), this indicates that the dispersion is substantially homogenous.Dispersions of the present invention that are substantially homogeneousgenerally are more physically stable and have improvedconcentration-enhancing properties and, in turn improvedbioavailability, relative to nonhomogeneous dispersions.

The compositions comprising the CETP inhibitor andconcentration-enhancing polymer provide enhanced concentration of thedissolved CETP inhibitor in in vitro dissolution tests. It has beendetermined that enhanced drug concentration in in vitro dissolutiontests in Model Fasted Duodenal (MFD) solution or Phosphate BufferedSaline (PBS) is a good indicator of in vivo performance andbioavailability. An appropriate PBS solution is an aqueous solutioncomprising 20 mM sodium phosphate (Na₂HPO₄), 47 mM potassium phosphate(KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5 with NaOH. Anappropriate MFD solution is the same PBS solution wherein additionallyis present 7.3 mM sodium taurocholic acid and 1.4 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition of the present invention can be dissolution-tested by addingit to MFD or PBS solution and agitating to promote dissolution.Generally, the amount of composition added to the solution in such atest is an amount that, if all the drug in the composition dissolved,would produce a CETP inhibitor concentration that is at least about10-fold and preferably at least 100-fold the equilibrium solubility ofthe CETP inhibitor alone in the test solution. To demonstrate evenhigher levels of dissolved CETP inhibitor concentration, addition ofeven larger amounts of the composition is desirable.

In one aspect, the compositions of the present invention provide aMaximum Drug Concentration (MDC) that is at least about 10-fold theequilibrium concentration of a control composition comprising anequivalent quantity of CETP inhibitor but free from the polymer. Inother words, if the equilibrium concentration provided by the controlcomposition is 1 μg/mL, then a composition of the present inventionprovides an MDC of at least about 10 μg/mL. The control composition isconventionally the undispersed CETP inhibitor alone (e.g., typically,the crystalline CETP inhibitor alone in its most thermodynamicallystable crystalline form, or in cases where a crystalline form of theCETP inhibitor is unknown, the control may be the amorphous CETPinhibitor alone) or the CETP inhibitor plus a weight of inert diluentequivalent to the weight of polymer in the test composition. It is to beunderstood that the control composition is free from solubilizers orother components which would materially affect the solubility of theCETP inhibitor, and that the CETP inhibitor is in solid form in thecontrol composition. Preferably, the MDC of CETP inhibitor achieved withthe compositions of the present invention is at least about 50-fold,more preferably at least about 200-fold and even more preferably atleast about 500-fold, the equilibrium concentration of the controlcomposition. Surprisingly, the present invention may achieve extremelylarge enhancements in aqueous concentration. In some cases, the MDC ofCETP inhibitor provided by the compositions of the present invention are200-fold to more than 1000-fold the equilibrium concentration of thecontrol composition. For some CETP inhibitors, due to their extremelylow aqueous solubilites, such large enhancements are required in orderfor the inhibitors to be sufficiently bioavailable when orally dosed.

Alternatively, the compositions of the present invention provide an MDCthat is greater than the MDC of the control composition. The MDCprovided by the composition comprising a CETP inhibitor and aconcentration-enhancing polymer may be 10-, 50-, 200- or 500-fold theMDC provided by a control composition.

Alternatively, the compositions of the present invention provide in anaqueous use environment a concentration versus time Area Under The Curve(AUC), for any period of at least 90 minutes between the time ofintroduction into the use environment and about 270 minutes followingintroduction to the use environment, that is at least 5-fold that of acontrol composition comprising an equivalent quantity of undispersedCETP inhibitor. Preferably, the compositions of the present inventionprovide in an aqueous use environment a concentration versus time AUC,for any period of at least 90 minutes between the time of introductioninto the use environment and about 270 minutes following introduction tothe use environment, that is at least about 25-fold, more preferably atleast about 100-fold and even more preferably at least about 250-foldthat of a control composition as described above. Such largeenhancements in aqueous concentration versus time AUC values aresurprising given the extremely low aqueous solubility and hydrophobicityof most CETP inhibitors.

A typical in vitro test to evaluate enhanced drug concentration inaqueous solution can be conducted by (1) adding with agitation asufficient quantity of control composition, typically the CETP inhibitoralone, to the in vitro test medium, typically MFD or PBS solution, toachieve equilibrium concentration of the CETP inhibitor; (2) adding withagitation a sufficient quantity of test composition (e.g., the CETPinhibitor and polymer) in an equivalent test medium, such that if allthe CETP inhibitor dissolved, the theoretical concentration of CETPinhibitor would exceed the equilibrium concentration of the CETPinhibitor by a factor of at least 10, and preferably a factor of atleast 100; and (3) comparing the measured MDC and/or aqueousconcentration versus time AUC of the test composition in the test mediumwith the equilibrium concentration, and/or the aqueous concentrationversus time AUC of the control composition. In conducting such adissolution test, the amount of test composition or control compositionused is an amount such that if all of the CETP inhibitor dissolved theCETP inhibitor concentration would be at least 10-fold and preferably atleast 100-fold that of the equilibrium concentration. Indeed, for someextremely insoluble CETP inhibitors, in order to identify the MDCachieved it may be necessary to use an amount of test composition suchthat if all of the CETP inhibitor dissolved, the CETP inhibitorconcentration would be 10,000-fold or even more, that of the equilibriumconcentration of the CETP inhibitor.

The concentration of dissolved CETP inhibitor is typically measured as afunction of time by sampling the test medium and plotting CETP inhibitorconcentration in the test medium vs. time so that the MDC can beascertained. The MDC is taken to be the maximum value of dissolved CETPinhibitor measured over the duration of the test. The aqueousconcentration of the CETP inhibitor versus time AUC is calculated byintegrating the concentration versus time curve over any 90-minute timeperiod between the time of introduction of the composition into theaqueous use environment (time equals zero) and 270 minutes followingintroduction to the use environment (time equals 270 minutes).Typically, when the composition reaches its MDC rapidly, less than about30 minutes, the time interval used to calculate AUC is from time equalszero to time equals 90 minutes. However, if the AUC over any 90-minutetime period described above of a composition meets the criterion of thisinvention, then the composition is a part of this invention.

To avoid large CETP inhibitor particulates which would give an erroneousdetermination, the test solution is either filtered or centrifuged.“Dissolved CETP inhibitor” is typically taken as that material thateither passes a 0.45 μm syringe filter or, alternatively, the materialthat remains in the supernatant following centrifugation. Filtration canbe conducted using a 13 mm, 0.45 μm polyvinylidine difluoride syringefilter sold by Scientific Resources under the trademark TITAN®.Centrifugation is typically carried out in a polypropylenemicrocentrifuge tube by centrifuging at 13,000 G for 60 seconds. Othersimilar filtration or centrifugation methods can be employed and usefulresults obtained. For example, using other types of microfilters mayyield values somewhat higher or lower (±10-40%) than that obtained withthe filter specified above but will still allow identification ofpreferred dispersions. It is recognized that this definition of“dissolved CETP inhibitor” encompasses not only monomeric solvated CETPinhibitor molecules but also a wide range of species such aspolymer/CETP inhibitor assemblies that have submicron dimensions such asCETP inhibitor aggregates, aggregates of mixtures of polymer and CETPinhibitor, micelles, polymeric micelles, colloidal particles ornanocrystals, polymer/CETP inhibitor complexes, and other such CETPinhibitor-containing species that are present in the filtrate orsupernatant in the specified dissolution test.

Alternatively, the compositions of the present invention, when dosedorally to a human or other animal, provide an AUC in CETP inhibitorconcentration in the blood that is at least about 4-fold that observedwhen a control composition comprising an equivalent quantity ofundispersed drug is dosed. It is noted that such compositions can alsobe said to have a relative bioavailability of about 4. Preferably, thecompositions of the present invention, when dosed orally to a human orother animal, provide an AUC in CETP inhibitor concentration in theblood that is at least about 6-fold, more preferably at least about10-fold, and even more preferably at least about 20-fold that observedwhen a control composition comprising an equivalent quantity ofundispersed drug is dosed. It is to be understood that when dosed invivo, the dosing vehicle does not contain any solubilizer or othercomponents which would materially affect the solubility of the CETPinhibitor, and that the CETP inhibitor is in solid form in the controlcomposition. An exemplary dosing vehicle would be a suspension solutionof water containing 0.5 wt % hydroxypropyl cellulose (such as METHOCEL)and 0.16 wt % of the surfactant polyoxyethylene 20 sorbitan monooleate(such as TWEEN 80). Thus, the compositions of the present invention canbe evaluated in either in vitro or in vivo tests, or both.

Relative bioavailability of CETP inhibitors in the dispersions of thepresent invention can be tested in vivo in animals or humans usingconventional methods for making such a determination. An in vivo test,such as a crossover study, may be used to determine whether acomposition of CETP inhibitor and concentration-enhancing polymerprovides an enhanced relative bioavailability compared with a controlcomposition comprised of a CETP inhibitor but no polymer as describedabove. In an in vivo crossover study a “test composition” of CETPinhibitor and polymer is dosed to half a group of test subjects and,after an appropriate washout period (e.g., one week) the same subjectsare dosed with a “control composition” that comprises an equivalentquantity of CETP inhibitor as the “test composition” (but with nopolymer present). The other half of the group is dosed with the controlcomposition first, followed by the test composition. The relativebioavailability is measured as the concentration in the blood (serum orplasma) versus time area under the curve (AUC) determined for the testgroup divided by the AUC in the blood provided by the controlcomposition. Preferably, this test/control ratio is determined for eachsubject, and then the ratios are averaged over all subjects in thestudy. In vivo determinations of AUC can be made by plotting the serumor plasma concentration of drug along the ordinate (y-axis) against timealong the abscissa (x-axis). It is to be understood by those skilled inthe art that such in vivo tests are conventionally carried out underfasted conditions.

Thus, as noted above, one embodiment of the present invention is one inwhich the relative bioavailability of the test composition is at leastabout 4 relative to a control composition comprised of a CETP inhibitorbut with no polymer as described above. (That is, the in vivo AUCprovided by the test composition is at least about 4-fold the in vivoAUC provided by the control composition.) A preferred embodiment of theinvention is one in which the relative bioavailability of the testcomposition is at least about 6, and even more preferably at least about10 relative to a control composition composed of the CETP inhibitor butwith no polymer present, as described above. The determination of AUCsis a well-known procedure and is described, for example, in Welling,“Pharmacokinetics Processes and Mathematics,” ACS Monograph 185 (1986).

The compositions of the present invention have particular utility whenthe “absolute bioavailability” of the CETP inhibitor is less than about5%, and even greater utility when the absolute bioavailability is lessthan about 1%. By “absolute bioavailability” is meant the ratio of thearea under the blood plasma or serum drug concentration versus timecurve for oral dosing of a test composition to that obtained byintravenous dosing of a solution of the CETP inhibitor. Care must betaken when determining the absolute bioavailability of CETP inhibitorsbecause their low solubility can result in precipitation of thecrystalline form when dosed intravenously, leading to an inaccuratecalculation of absolute bioavailability. For CETP inhibitors with suchabsolute bioavailabilities less than about 5%, the compositions of thepresent invention preferably provide a relative bioavailability that isat least about 6-fold relative to a control composition comprised of theCETP inhibitor but with no polymer present, as described above. Morepreferably, when the absolute bioavailability of the CETP inhibitor isless than about 1%, the compositions of the present invention providerelative bioavailability that is at least about 10-fold, and even morepreferably at least about 20-fold relative to a control composition, asdescribed above.

Cholesteryl Ester Transfer Protein Inhibitors

The invention is useful for CETP inhibitors which have sufficiently lowaqueous solubility, low bioavailability or slow rate of absorption suchthat it is desirable to increase their concentration in an aqueousenvironment of use. Therefore, anytime one finds it desirable to raisethe aqueous concentration of the CETP inhibitor in a use environment,the invention will find utility. The CETP inhibitor is “substantiallywater-insoluble” which means that the CETP inhibitor has a minimumaqueous solubility of less than about 0.01 mg/mL (or 10 μg/ml) at anyphysiologically relevant pH (e.g., pH 1-8) and at about 22° C. (Unlessotherwise specified, reference to aqueous solubility herein and in theclaims is determined at about 22° C.) Compositions of the presentinvention find greater utility as the solubility of the CETP inhibitorsdecreases, and thus are preferred for CETP inhibitors with solubilitiesless than about 2 μg/mL, and even more preferred for CETP inhibitorswith solubilities less than about 0.5 μg/mL. Many CETP inhibitors haveeven lower solubilities (some even less than 0.1 μg/mL), and requiredramatic concentration enhancement to be sufficiently bioavailable uponoral dosing for effective plasma concentrations to be reached atpractical doses.

In general, it may be said that the CETP inhibitor has a dose-to-aqueoussolubility ratio greater than about 100 mL, where the solubility (mg/mL)is the minimum value observed in any physiologically relevant aqueoussolution (e.g., those with pH values from 1 to 8) including USPsimulated gastric and intestinal buffers, and dose is in mg.Compositions of the present invention, as mentioned above, find greaterutility as the solubility of the CETP inhibitor decreases and the doseincreases. Thus, the compositions are preferred as thedose-to-solubility ratio increases, and thus are preferred fordose-to-solubility ratios greater than 1000 mL, and more preferred fordose-to-solubility ratios greater than about 5000 ml. Thedose-to-solubility ratio may be determined by dividing the dose (in mg)by the aqueous solubility (in mg/ml).

Oral delivery of many CETP inhibitors is particularly difficult becausetheir aqueous solubility is usually extremely low, typically being lessthan 2 μg/ml, often being less than 0.1 μg/ml. Such low solubilities area direct consequence of the particular structural characteristics ofspecies that bind to CETP and thus act as CETP inhibitors. This lowsolubility is primarily due to the hydrophobic nature of CETPinhibitors. Clog P, defined as the base 10 logarithm of the ratio of thedrug solubility in octanol to the drug solubility in water, is a widelyaccepted measure of hydrophobicity. In general, Clog P values for CETPinhibitors are greater than 4 and are often greater than 5 to 7. Thus,the hydrophobic and insoluble nature of CETP inhibitors as a class posea particular challenge for oral delivery. Achieving therapeutic druglevels in the blood by oral dosing of practical quantities of druggenerally requires a large enhancement in drug concentrations in thegastrointestinal fluid and a resulting large enhancement inbioavailability. Such enhancements in drug concentration ingastrointestsinal fluid typically need to be at least about 10-fold andoften at least about 50-fold or even at least about 200-fold to achievedesired blood levels. Surprisingly, the dispersions of the presentinvention have proven to have the required large enhancements in drugconcentration and bioavailability.

In contrast to conventional wisdom, the relative degree of enhancementin aqueous concentration and bioavailability generally improves for CETPinhibitors as solubility decreases and hydrophobocity increases. Infact, the inventors have recognized a subclass of these CETP inhibitorsthat are essentially aqueous insoluble, highly hydrophobic, and arecharacterized by a set of physical properties. This subclass exhibitsdramatic enhancements in aqueous concentration and bioavailability whenformulated using the compositions of the present invention.

The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

A second property is a very high does-to-solubility ratio. Extremely lowsolubility often leads to poor or slow absorption of the drug from thefluid of the gastrointestinal tract, when the drug is dosed orally in aconventional manner. For extremely low solubility drugs, poor absorptiongenerally becomes progressively more difficult as the dose (mass of druggiven orally) increases. Thus, a second property of this subclass ofessentially insoluble, hydrophobic CETP inhibitors is a very high dose(in mg) to solubility (in mg/ml) ratio (ml). By “very highdose-to-solubility ratio” is meant that the dose-to-solubility ratio hasa value of at least 1000 ml, and preferably at least 5,000 ml, and morepreferably at least 10,000 ml.

A third property of this subclass of essentially insoluble, hydrophobicCETP inhibitors is that they are extremely hydrophobic. By extremelyhydrophobic is meant that the Clog P value of the drug, has a value ofat least 4.0, preferably a value of at least 5.0, and more preferably avalue of at least 5.5.

A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

Primarily, as a consequence of some or all of these four properties,CETP inhibitors of this subclass typically have very low absolutebioavailabilities. Specifically, the absolute bioavailibility of drugsin this subclass when dosed orally in their undispersed state is lessthan about 10% and more often less than about 5%.

For this subclass of CETP inhibitors, the CETP inhibitor, when dispersedin the dispersion, should be at least substantially amorphous, and morepreferably is almost completely amorphous. In addition, the dispersionshould be substantially homogeneous. As discussed below, suchdispersions may be made by mechanical processes, such as milling andextrusion; melt processes, such as fusion, melt-extrusion, andmelt-congealing; and solvent processes, such as non-solventprecipitation, spray coating, and spray-drying. When prepared in thisfashion, this class of essentially insoluble, hydrophobic CETPinhibitors often exhibits dramatic enhancements in aqueous concentrationin the use environment and in bioavailability when dosed orally. Whilethe degree of enhancement will depend on the particularconcentration-enhancing polymer, when preferred concentration-enhancingpolymers are used (as discussed below), such compositions may provide aMDC in an aqueous use environment that is at least about 50-fold, andpreferably at least about 200-fold, the equilibrium concentration of acontrol composition comprising an equivalent quantity of the essentiallyinsoluble, hydrophobic CETP inhibitor but free from theconcentration-enhancing polymer. Likewise, the compositions also displayin an aqueous use environment an AUC, for any period of at least 90minutes between the time of introduction into the use environment andabout 270 minutes following introduction into the use environment thatis at least about 25-fold, and preferably at least about 100-fold, thatof the control composition comprising an equivalent quantity of drug butfree from the concentration-enhancing polymer.

Turning now to the chemical structures of specific CETP inhibitors, oneclass of CETP inhibitors that finds utility with the present inventionconsists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

and pharmaceutically acceptable forms thereof;wherein R_(I-1) is hydrogen, Y_(I), W_(I)-X_(I), W_(I)-Y_(I);wherein W_(I) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(I) is —O—Y_(I), —S—Y_(I), —N(H)—Y_(I) or —N—(Y_(I))₂;

wherein Y_(I) for each occurrence is independently Z_(I) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(I-3) is hydrogen or Q_(I);

wherein Q_(I) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N— or di-N,N—(C₁-C₆)alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(I-4) is Q_(I-1) or V_(I-1)

wherein Q_(I-1) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I-1);

wherein V_(I-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(I-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(I-3) must contain V_(I) or R_(I-4) must containV_(I-1); and R_(I-5), R_(I-6), R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

Compounds of Formula I are disclosed in commonly assigned U.S. Pat. No.6,140,342, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula I:

-   [2R,4S]4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid 2,2,2-trifluoro-ethylester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic    acid methyl ester;-   [2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic    acid methyl ester;-   [2R,4S](3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic    acid methyl ester, hydrochloride

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

and pharmaceutically acceptable forms thereof;

wherein R_(II-1) is hydrogen, Y_(II), W_(II)-X_(II), W_(II)-Y_(II);

wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II) or —N—(Y_(II))₂;

wherein Y_(II) for each occurrence is independently Z_(II) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

Z_(II) is a partially saturated, fully saturated or fully unsaturatedthree to twelve membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines;

R_(II-3) is hydrogen or Q_(II);

wherein Q_(II) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II);

wherein V_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(II) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

R_(II-4) is Q_(II-1) or V_(II-1)

wherein Q_(II-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

wherein V_(II-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(II-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

wherein either R_(II-3) must contain V_(II) or R_(II-4) must containV_(II-1); and

R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(II) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon may optionallybe replaced with one or two heteroatoms selected independently fromoxygen, sulfur and nitrogen wherein said carbon atoms are optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

wherein T_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

provided that at least one of substituents R_(II-5), R_(II-6), R_(II-7)and R_(II-8) is not hydrogen and is not linked to the quinoline moietythrough oxy.

Compounds of Formula II are disclosed in commonly assigned U.S. Pat. No.6,147,090, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula II:

-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester.-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula III

and pharmaceutically acceptable forms thereof;

wherein R_(III-1) is hydrogen, Y_(III), W_(III)-X_(III),W_(III)-Y_(III);

wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(III) is —O—Y_(III), —N(H)—Y_(III) or —N—(Y_(III))₂;

Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

wherein Z_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

R_(III-3) is hydrogen or Q_(III);

wherein Q_(III) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

wherein V_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(III) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

R_(III-4) is Q_(III-1) or V_(III-1);

wherein Q_(III-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III-1);

wherein V_(III-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(III-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

wherein either R_(III-3) must contain V_(III) or R_(III-4) must containV_(III-1); and

R_(III-5) and R_(III-6), or R_(III-6) and R_(III-7), and/or R_(III-7)and R_(III-8) are taken together and form at least one four to eightmembered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent optionally having from one to nine fluorines;

provided that the R_(III-5), R_(III-6), R_(III-7) and/or R_(III-8), asthe case may be, that do not form at least one ring are eachindependently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

Compounds of Formula III are disclosed in commonly assigned pending U.S.Pat. No. 6,147,089, the complete disclosure of which is hereinincorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula III:

-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic    acid ethyl ester;-   [6R,8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylic    acid ethylester;-   [6R,8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylic    acid propyl ester;-   [7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylic    acid ethyl ester; and-   [6S,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylic    acid ethyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

and pharmaceutically acceptable forms thereof;wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)-X_(IV) or W_(IV)-Y_(IV);wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

wherein Y_(IV) for each occurrence is independently Z_(IV) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(IV-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(IV-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

with the proviso that R_(IV-2) is not methyl;

R_(IV-3) is hydrogen or Q_(IV);

wherein Q_(IV) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(IV) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(IV-4) is Q_(IV-1) or V_(IV-1);

wherein Q_(IV-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV-1);

wherein V_(IV-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(IV-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) must containV_(IV-1);

R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(IV) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon, mayoptionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/or R_(IV-7)and R_(IV-8) may also be taken together and can form at least one fourto eight membered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(IV-5) and R_(IV-6), or R_(IV-6)and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R_(IV-2) is carboxyl or(C₁-C₄)alkylcarboxyl, then R_(IV-1) is not hydrogen.

Compounds of Formula IV are disclosed in commonly assigned U.S. Pat. No.6,197,786, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula IV:

-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinaline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester,-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid 2-hydroxy-ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester; and-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

and pharmaceutically acceptable forms thereof;wherein R_(V-1) is Y_(V), W_(V)-X_(V) or W_(V)-Y_(V);wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(V) is —O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or —N—(Y_(V))₂;

wherein Y_(V) for each occurrence is independently Z_(V) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(V-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(V-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

R_(V-3) is hydrogen or Q_(V);

wherein Q_(V) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1),(C₁-C₄)alkyleneV_(V-1) or V_(V-2);

wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

wherein V_(V-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, oxo, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein V_(V-2) is a partially saturated, fully saturated or fullyunsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

wherein R_(V-4) does not include oxycarbonyl linked directly to the C₄nitrogen;

wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

R_(V-5), R_(V-6), R_(V-2) and R_(V-8) are independently hydrogen, abond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₁₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/or R_(V-7) andR_(V-8) may also be taken together and can form at least one ring thatis a partially saturated or fully unsaturated four to eight memberedring optionally having one to three heteroatoms independently selectedfrom nitrogen, sulfur and oxygen;

wherein said rings formed by R_(V-5) and R_(V-6), or R_(V-6) andR_(V-7), and/or R_(V-7) and R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

Compounds of Formula V are disclosed in commonly assigned U.S. Pat. No.6,140,343, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula V:

-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester; and-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of cycloalkano-pyridines having the Formula VI

and pharmaceutically acceptable forms thereof;in which

A_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(VI-3)R_(VI-4), wherein

R_(VI-3) and R_(VI-4) are identical or different and denote a hydrogen,phenyl or a straight-chain or branched alkyl containing up to 6 carbonatoms,

D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)-L_(VI)-,

or R_(VI-9)-T_(VI)-V_(VI)-X_(VI), wherein

R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from one another,a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to10 carbon atom or a 5- to 7-membered, optionally benzo-condensed,saturated or unsaturated, mono-, bi- or tricyclic heterocycle containingup to 4 heteroatoms from the series of S, N and/or O, wherein the ringsare optionally substituted, in the case of the nitrogen-containing ringsalso via the N function, with up to five identical or differentsubstituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl,cyano, carboxyl, trifluoromethoxy, a straight-chain or branched acyl,alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to6 carbon atoms each, an aryl or trifluoromethyl-substituted arylcontaining 6 to 10 carbon atoms each, or an optionally benzo-condensed,aromatic 5- to 7-membered heterocycle containing up to 3 heteoatoms fromthe series of S, N and/or O, and/or in the form of a group according tothe formula —OR_(VI-10), —SR_(VI-11), —SO₂R_(VI-12) or—NR_(VI-13)R_(VI-14), wherein

R_(VI-10), R_(VI-11) and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(VI-13) and R_(VI-14) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-5) and/or R_(VI-6) denote a radical according to the formula

R_(VI-7) denotes a hydrogen or halogen, and

R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl,trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula

—NR_(VI-15)R_(VI-16)

wherein

R_(VI-15) and R_(VI-16) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-7) and R_(VI-8) together form a radical according to the formula═O or ═NR_(VI-17), wherein

R_(VI-17) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each,

L_(VI) denotes a straight-chain or branched alkylene or alkenylene chaincontaining up to 8 carbon atoms each, which are optionally substitutedwith up to two hydroxyl groups,

T_(VI) and X_(VI) are identical or different and denote a straight-chainor branched alkylene chain containing up to 8 carbon atoms, or

T_(VI) or X_(VI) denotes a bond,

V_(VI) denotes an oxygen or sulfur atom or an —NR_(VI-18) group, wherein

R_(VI-18) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl,

E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl,

R_(VI-1) and R_(VI-2) together form a straight-chain or branchedalkylene chain containing up to 7 carbon atoms, which must besubstituted with a carbonyl group and/or a radical according to theformula

wherein

a and b are identical or different and denote a number equaling 1, 2 or3,

R_(VI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbonatoms, a straight-chain or branched silylalkyl containing up to 8 carbonatoms, or a straight-chain or branched alkyl containing up to 8 carbonatoms, which is optionally substituted with a hydroxyl, a straight-chainor a branched alkoxy containing up to 6 carbon atoms or a phenyl, whichmay in turn be substituted with a halogen, nitro, trifluoromethyl,trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkylthat is optionally substituted with a group according to the formula—OR_(VI-22), wherein

R_(VI-22) denotes a straight-chain or branched acyl containing up to 4carbon atoms or benzyl, or

R_(VI-19) denotes a straight-chain or branched acyl containing up to 20carbon atoms or benzoyl, which is optionally substituted with a halogen,trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain orbranched fluoroacyl containing up to 8 carbon atoms,

R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or

R_(VI-20) and R_(VI-21) together form a 3- to 6-membered carbocyclicring, and a the carbocyclic rings formed are optionally substituted,optionally also geminally, with up to six identical or differentsubstituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen,carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl,alkoxy or alkylthio containing up to 6 carbon atoms each, or astraight-chain or branched alkyl containing up to 6 carbon atoms, whichis in turn substituted with up to two identical or differentsubstituents in the form of a hydroxyl, benzyloxy, trifluoromethyl,benzoyl, a straight-chain or branched alkoxy, oxyacyl or carboxylcontaining up to 4 carbon atoms each and/or a phenyl, which may in turnbe substituted with a halogen, trifluoromethyl or trifluoromethoxy,and/or the carbocyclic rings formed are optionally substituted, alsogeminally, with up to five identical or different substituents in theform of a phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turnare optionally substituted with a halogen, trifluoromethyl,trifluoromethoxy or nitro, and/or optionally in the form of a radicalaccording to the formula

-   -   —SO₂—C₆H₅, —(CO)_(d)NR_(VI-23)R_(VI-24) or ═O,        wherein

c is a number equaling 1, 2, 3 or 4,

d is a number equaling 0 or 1,

R_(VI-23) and R_(VI-24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

wherein

W_(VI) denotes either an oxygen atom or a sulfur atom,

Y_(VI) and Y′_(VI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

f is a number equaling 1 or 2,

R_(VI-25), R_(VI-26), R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30) andR_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together denotea straight-chain or branched alkyl chain containing up to 6 carbon atomsor

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together form aradical according to the formula

wherein

W_(VI) has the meaning given above,

g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

R_(VI-32) and R_(VI-33) together form a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group according to theformula SO, SO₂ or —NR_(VI-34), wherein

R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or a straight-chainor branched alkyl containing up to 4 carbon atoms, and salts and Noxides thereof, with the exception of 5(6H)-quinolones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

Compounds of Formula VI are disclosed in European Patent Application No.EP 818448 A1, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula VI:

-   2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;-   2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;-   [2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;-   [5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;-   [5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;-   5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;-   2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted-pyridines having the Formula VII

and pharmaceutically acceptable forms thereof, wherein

R_(VII-2) and R_(VII-6) are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinatedaralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that atleast one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

R_(VII-3) is selected from the group consisting of hydroxy, amido,arylcarbonyl, heteroarylcarbonyl, hydroxymethyl —CHO,

—CO₂R_(VII-7), wherein R_(VII-7) is selected from the group consistingof hydrogen, alkyl and cyanoalkyl; and

wherein R_(VII-15a) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy and heterocyclyloxy, and

R_(VII-16a) is selected from the group consisting of alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, andheterocyclyl, arylalkoxy, trialkylsilyloxy;

R_(VII-4) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl,

—SO₂R_(VII-9), wherein R_(VII-9) is selected from the group consistingof hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-10a) and R_(VII-10b)are independently selected from the group consisting of hydrogen,hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and—OP(S)(OR_(VII-11a)) (OR_(VII-11b)), wherein R_(VII-11a) and R_(VII-11b)are independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

R_(VII-5) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-15b) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(VII-16b) is selected form the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

wherein R_(VII-17) and R_(VII-18) are independently selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

wherein R_(VII-19) is selected from the group consisting of alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and R_(VII-22)CO₂R_(VII-23), wherein

R_(VII-20) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl,alkylheteroarylamino, arylheteroarylamino,

R_(VII-21) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl,

R_(VII-22) is selected from the group consisting of alkylene or arylene,and

R_(VII-23) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R_(VII-24) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, aralkenyl, and aralkynyl;

wherein R_(VII-25) is heterocyclylidenyl;

wherein R_(VII-26) and R_(VII-27) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-28) and R_(VII-29) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-30) and R_(VII-31) are independently alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R_(VII-32) and R_(VII-33) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-36) is selected from the group consisting of alkyl,alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-37) and R_(VII-38) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-39) is selected from the group consisting of hydrogen,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio andheterocyclylthio, and

R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;

—N═R_(VII-41),

wherein R_(VII-41) is heterocyclylidenyl;

wherein R_(VII-42) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R_(VII-43) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

wherein R_(VII-44) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

—N═S═O;

—N═C═S;

N═C═O;

—N₃;

—SR_(VII-45)

wherein R_(VII-45) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl,heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl,alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl,heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl,aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl,aminocarbonylheteroaryl, and aminocarbonylheterocyclyl,

—SR_(VII-46), and —CH₂R_(VII-47),

wherein R_(VII-46) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R_(VII-47) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R_(VII-48) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,and

R_(VII-49) is selected from the group consisting of alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R_(VII-50) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R_(VII-51) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

wherein R_(VII-53) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

provided that when R_(VII-5) is selected from the group consisting ofheterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical ofthe corresponding heterocyclylalkyl or heterocyclylalkenyl is other thanδ-lactone; and

provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl, andone of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VII-6) is difluoromethyl.

Compounds of Formula VII are disclosed in WO 9941237-A1, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula VII:

-   Dimethyl    5,5′-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted pyridines and biphenyls having theFormula VIII

and pharmaceutically acceptable forms thereof,in which

A_(VIII) stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-1)R_(VIII-2), wherein

R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

D_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

E_(VIII) and L_(VIII) are either identical or different and stand forstraight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by cycloalkyl with 3 to 8 carbon atoms, or standsfor cycloalkyl with 3 to 8 carbon atoms, or

E_(VIII) has the above-mentioned meaning and

L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms, whichis optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-3)R_(VIII-4), wherein

R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

E_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, or stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-5)R_(VIII-6), wherein

R_(VIII-5) and R_(VIII-6) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), and

L_(VIII) in this case stands for straight-chain or branched alkoxy withup to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms,

T_(VIII) stands for a radical of the formula

R_(VIII-7)—X_(VIII)— or

wherein

R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, orthiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula

—NR_(VIII-11)R_(VIII-12), wherein

R_(VIII-11) and R_(VIII-12) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2),

X_(VIII) denotes a straight or branched alkyl chain or alkenyl chainwith 2 to 10 carbon atoms each, which are optionally substituted up to 2times by hydroxy,

R_(VIII-9) denotes hydrogen, and

R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to5 carbon atoms, or a radical of the formula

—NR_(VIII-13)R_(VIII-14), wherein

R_(VIII-13) and R_(VIII-14) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

R_(VIII-9) and R_(VIII-10) form a carbonyl group together with thecarbon atom.

Compounds of Formula VIII are disclosed in WO 9804528, the completedisclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted 1,2,4-triazoles having the Formula IX

and pharmaceutically acceptable forms thereof;

wherein R_(IX-1) is selected from higher alkyl, higher alkenyl, higheralkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl,arylthioalkyl, and cycloalkylalkyl;

wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl, andcycloalkenyl, wherein

R_(IX-2) is optionally substituted at a substitutable position with oneor more radicals independently selected from alkyl, haloalkyl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy,aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino anddialkylamino; and

wherein R_(IX-3) is selected from hydrido, —SH and halo; providedR_(IX-2) cannot be phenyl or 4-methylphenyl when R_(IX-1) is higheralkyl and when R_(IX-3) is —SH.

Compounds of Formula IX are disclosed in WO 9914204, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula IX:

-   2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;-   4-(3-chloro-4-methylphenyl)-2.4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;    and-   2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

Another class of CETP inhibitors that finds utility with the presentinvention consists of hetero-tetrahydroquinolines having the Formula X

N-oxides of said compounds, and pharmaceutically acceptable formsthereof;in which

A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5- to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or O, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula —NR_(X-3)R_(X-4), in which

R_(X-3) and R_(X-4) are identical or different and denote hydrogen,phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,or

A_(X) represents a radical of the formula

D_(X) represents an aryl having 6 to 10 carbon atoms, that is optionallysubstituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

R_(X-5)-L_(X)-,

or R_(X-9)-T_(X)-V_(X)—X_(X)—

in which

R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringfrom the series consisting of S, N and/or O, in which the rings aresubstituted, optionally, in case of the nitrogen containing aromaticrings via the N function, with up to 5 identical or differentsubstituents in the form of halogen, trifluoromethyl, nitro, hydroxy,cyano, carbonyl, trifluoromethoxy, straight straight-chain or branchedacyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl eachhaving up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryleach having 6 to 10 carbon atoms or by an, optionally benzo-condensed,aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatomsfrom the series consisting of S, N, and/or O, and/or substituted by agroup of the formula —OR_(X-10), —SR_(X-11), SO₂R_(X-12) or—NR_(X-13)R_(X-14),

in which

R_(X-10), R_(X-11) and R_(X-12) independently from each other denotearyl having 6 to 10 carbon atoms, which is in turn substituted with upto 2 identical or different substituents in the form of phenyl, halogenor a straight-chain or branched alkyl having up to 6 carbon atoms,

R_(X-13) and R_(X-14) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above,

or

R_(X-5) and/or R_(X-6) denote a radical of the formula

R_(X-7) denotes hydrogen or halogen, and

R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl having upto 6 carbon atoms or a radical of the formula

—NR_(X-15)R_(X-16),

in which

R_(X-15) and R_(X-16) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above,

or

R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17),

in which

R_(X-17) denotes hydrogen or straight chain or branched alkyl, alkoxy oracyl having up to 6 carbon atoms,

L_(x) denotes a straight chain or branched alkylene or alkenylene chainhaving up to 8 carbon atoms, that are optionally substituted with up to2 hydroxy groups,

T_(X) and X_(X) are identical or different and denote a straight chainor branched alkylene chain with up to 8 carbon atoms or

T_(X) or X_(X) denotes a bond,

V_(X) represents an oxygen or sulfur atom or an —NR_(X-18)-group, inwhich

R_(X-18) denotes hydrogen or straight chain or branched alkyl with up to6 carbon atoms or phenyl,

E_(X) represents cycloalkyl with 3 to 8 carbon atoms, or straight chainor branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

R_(X-1) and R_(X-2) together form a straight-chain or branched alkylenechain with up to 7 carbon atoms, that must be substituted by carbonylgroup and/or by a radical with the formula

in which a and b are identical or different and denote a number equaling1,2, or 3,

R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbon atoms,straight chain or branched silylalkyl with up to 8 carbon atoms orstraight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula —OR_(X-22),

in which

R_(X-22) denotes a straight chain or branched acyl with up to 4 carbonatoms or benzyl,

or

R_(X-19) denotes straight chain or branched acyl with up to 20 carbonatoms or benzoyl, that is optionally substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(X-20) and R_(X-21) are identical or different and denote hydrogen,phenyl or straight chain or branched alkyl with up to 6 carbon atoms,

or

R_(X-20) and R_(X-21) together form a 3- to 6-membered carbocyclic ring,and the carbocyclic rings formed are optionally substituted, optionallyalso geminally, with up to six identical or different substituents inthe form of trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro,azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each,by straight chain or branched alkoxycarbonyl, alkoxy or alkylthio withup to 6 carbon atoms each or by straight chain or branched alkyl with upto 6 carbon atoms, which in turn is substituted with up to 2 identicallyor differently by hydroxyl, benzyloxy, trifluoromethyl, benzoyl,straight chain or branched alkoxy, oxyacyl or carbonyl with up to 4carbon atoms each and/or phenyl, which may in turn be substituted with ahalogen, trifluoromethyl or trifluoromethoxy, and/or the formedcarbocyclic rings are optionally substituted, also geminally, with up to5 identical or different substituents in the form of phenyl, benzoyl,thiophenyl or sulfonylbenzyl, which in turn are optionally substitutedby halogen, trifluoromethyl, trifluoromethoxy or nitro, and/oroptionally are substituted by a radical with the formula

-   -   —SO₂—C₆H₅, —(CO)_(d)NR_(X-23)R_(X-24) or ═O,        in which

c denotes a number equaling 1, 2, 3, or 4,

d denotes a number equaling 0 or 1,

R_(X-23) and R_(X-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, that is optionallysubstituted with up to 2 identically or differently by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the formed carbocyclicrings are substituted optionally by a spiro-linked radical with theformula

in which

W_(X) denotes either an oxygen or a sulfur atom

Y_(X) and Y′_(X) together form a 2 to 6 membered straight chain orbranched alkylene chain,

e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,f denotes a number equaling 1 or 2,

R_(X-25), R_(X-26), R_(X-27), R_(X-28), R_(X-29), R_(X-30) and R_(X-31)are identical or different and denote hydrogen, trifluoromethyl, phenyl,halogen or straight chain or branched alkyl or alkoxy with up to 6carbon atoms each,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together form aradical with the formula

in which

W_(X) has the meaning given above,

g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

R_(X-32) and R_(X-33) form together a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group with the formula SO,SO₂ or π-NR_(X-34).

in which

R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branched alkylwith up to 4 carbon atoms.

Compounds of Formula X are disclosed in WO 9914215, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula X:

-   2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;-   2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;    and-   2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted tetrahydro naphthalines and analogouscompounds having the Formula XI

and pharmaceutically acceptable forms thereof, in which

A_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands foraryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula

—NR_(XI-3)R_(XI-4),

in which

R_(XI-3) and R_(XI-4) are identical or different and denote hydrogen,phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms

D_(XI) stands for a radical of the formula

R_(XI-5)-L_(XI)-,

or

R_(XI-9)-T_(XI)-V_(XI)—X_(XI)-

in which

R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other, denotecycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10 carbonatoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstituted—in the case of the nitrogen-containing rings also via theN-function-up to 5-fold, identical or different, by halogen,trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each. by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula

—OR_(XI-10), —SR_(XI-11), —SO₂R_(XI-12) or —NR_(XI-13)R_(XI-14),

in which

R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other, denotearyl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen. or by straight-chainor branched alkyl with up to 6 carbon atoms,

R_(XI-13) and R_(XI-14) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-5) and/or R_(XI-6) denote a radical of the formula

R_(XI-7) denotes hydrogen, halogen or methyl,

and

R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl with up to6 carbon atoms each, or a radical of the formula —NR_(XI-15)R_(XI-16).

in which

R_(XI-15) and R_(XI-16) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-7) and R_(XI-8) together form a radical of the formula ═O or═NR_(XI-17), in which

R_(XI-17) denotes hydrogen or straight-chain or branched alkyl, alkoxyor acyl with up to 6 carbon atoms each,

L_(XI) denotes a straight-chain or branched alkylene- or alkenylenechain with up to 8 carbon atoms each, which is possibly substituted upto 2-fold by hydroxy,

T_(XI) and X_(XI) are identical or different and denote a straight-chainor branched alkylene chain with up to 8 carbon atoms,

or

T_(XI) and X_(XI) denotes a bond,

V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18) group,

in which

R_(XI-18) denotes hydrogen or straight-chain or branched alkyl with upto 6 carbon atoms, or phenyl,

E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

in which

a and b are identical or different and denote a number 1, 2 or 3

R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula —OR_(XI-22),

in which

R_(XI-22) denotes straight-chain or branched acyl with up to 4 carbonatoms, or benzyl,

or

R_(XI-19) denotes straight-chain or branched acyl with up to 20 carbonatoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(XI-20) and R_(XI-21) are identical or different, denoting hydrogen,phenyl or straight-chain or branched alkyl with up to 6 carbon atoms,

or

R_(XI-20) and R_(XI-21) together form a 3- to 6-membered carbocycle,and, possibly also geminally, the alkylene chain formed by R_(XI-1) andR_(XI-2), is possibly substituted up to 6-fold, identical or different,by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido,cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, bystraight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with upto 6 carbon atoms each, or by straight-chain or branched alkyl with upto 6 carbon atoms, which itself is substituted up to 2-fold, identicalor different, by hydroxyl, benzyloxy, trifluoromethyl, benzoyl,straight-chain or branched alkoxy, oxyacyl or carboxyl with up to 4carbon atoms each, and/or phenyl—which itself can be substituted byhalogen, trifluoromethyl or trifluoromethoxy, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is substituted, also geminally, possiblyup to 5-fold, identical or different, by phenyl, benzoyl, thiophenyl orsulfobenzyl—which themselves are possibly substituted by halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by a radical ofthe formula

—SO₂—C₆H₅, —(CO)_(d)NR_(XI-23)R_(XI-24) or ═O,

in which

c denotes a number 1, 2, 3 or 4,

d denotes a number 0 or 1,

R_(XI-23) and R_(XI-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight-chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, which is possiblysubstituted up to 2-fold. identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

in which

W_(XI) denotes either an oxygen or a sulfur atom,

Y_(XI) and Y′_(XI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number 1, 2, 3, 4, 5, 6 or 7,

f denotes a number 1 or 2,

R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30) andR_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form astraight-chain or branched alkyl chain with up to 6 carbon atoms,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form aradical of the formula

in which

W_(XI) has the meaning given above,

g is a number 1, 2, 3, 4, 5, 6 or 7,

R_(XI-32) and R_(XI-33) together form a 3- to 7-membered heterocyclethat contains an oxygen- or sulfur atom or a group of the formula SO,SO₂ or —NR_(XI-34).

in whichR_(XI-34) denotes hydrogen, phenyl, benzyl, or straight-chain orbranched alkyl with up to 4 carbon atoms.

Compounds of Formula XI are disclosed in WO 9914174, the completedisclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 2-aryl-substituted pyridines having the FormulaXII

and pharmaceutically acceptable forms thereof, in which

A_(XII) and E_(XII) are identical or different and stand for aryl with 6to 10 carbon atoms which is possibly substituted, up to 5-fold identicalor different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy,nitro or by straight-chain or branched alkyl, acyl, hydroxy alkyl oralkoxy with up to 7 carbon atoms each, or by a group of the formula—NR_(XII-1)R_(XII-2), where

R_(XII-1) and R_(XII-2) are identical or different and are meant to behydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

D_(XII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

T_(XII) stands for a radical of the formula R_(XII-3)—X_(XII)— or

where

R_(XII-3) and R_(XII-4) are identical or different and are meant to becycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or a 5- to 7-membered aromatic, possibly benzocondensated heterocyclewith up to 3 heteroatoms from the series S, N and/or O, which arepossibly substituted up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turncan be substituted by halogen trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula —NR_(XII-7)R_(XII-8).

where

R_(XII-7) and R_(XII-8) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above,

X_(XII) is a straight-chain or branched alkyl or alkenyl with 2 to 10carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

R_(XII-5) stands for hydrogen,

and

R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formula—NR_(XII-9)R_(XII-10),

where

R_(XII-9) and R_(XII-10) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above,

or

R_(XII-5) and R_(XII-6), together with the carbon atom, form a carbonylgroup.

Compounds of Formula XII are disclosed in EP 796846-A1, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XII:

-   4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)-methyl]-5-(1-hydroxyethyl)pyridine;-   2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)-fluoromethyl]-3-hydroxymethyl)pyridine;    and-   2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethylphenyl)vinyl]-3-hydroxymethyl)pyridine.

Another class of CETP inhibitors that finds utility with the presentinvention consists of compounds having the Formula XIII

and pharmaceutically acceptable forms thereof, in which R_(XIII) is astraight chain or branched C₁₋₁₀ alkyl; straight chain or branched C₂₋₁₀alkenyl; halogenated C₁₋₄ lower alkyl; C₃₋₁₀ cycloalkyl that may besubstituted; C₅₋₈ cycloalkenyl that may be substituted; C₃₋₁₀ cycloalkylC₁₋₁₀ alkyl that may be substituted; aryl that may be substituted;aralkyl that may be substituted; or a 5- or 6-membered heterocyclicgroup having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms thatmay be substituted,

X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C₁₋₄ lower alkyl;halogenated C₁₋₄ lower alkyl; C₁₋₄ lower alkoxy; cyano group; nitrogroup; acyl; or aryl, respectively;

Y_(XIII) is —CO—; or —SO₂—; and

Z_(XIII) is a hydrogen atom; or mercapto protective group.

Compounds of Formula XIII are disclosed in WO 98/35937, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIII:

-   N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclopentanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide;-   propanethioic acid,    2-methyl-,S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;-   propanethioic acid,    2,2-dimethyl-,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;    and-   ethanethioic acid,    S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of polycyclic aryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

and pharmaceutically acceptable forms thereof, wherein:

n_(XIV) is an integer selected from 0 through 5;

R_(XIV-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

X_(XIV) is selected from the group consisting of O, H, F, S, S(O), NH,N(OH), N(alkyl), and N(alkoxy);

R_(XIV-16) is selected from the group consisting of hydrido, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is a covalent bond, nomore than one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is O, no more than one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XI-2) and K_(XIV-1) must be a covalent bond when two of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) are O and S, and no morethan four of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1)are N;

D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) andK_(XIV-2) is O, no more than one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) must be a covalent bond when two of D_(XIV-3),

D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no morethan four of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)and K_(XIV-2) are N;

R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R_(XIV-2) and R_(XIV-3) are taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 6 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, and a heterocyclyl having from 4 through 8 contiguous members;

R_(XIV-3) is selected from the group consisting of hydrido, hydroxy,halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino,acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

Y_(XIV) is selected from a group consisting of a covalent single bond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2 and (CH(R_(XIV-14)))_(gXIV)—W_(XIV)—(CH(R_(XIV-14)))_(pXIV)wherein _(gXIV) and _(pXIV) are integers independently selected from 0and 1;

R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

R_(XIV-14) and R_(XIV-14), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

W_(XIV) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

Z_(XIV) is independently selected from a group consisting of a covalentsingle bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is an integerselected from 1 and 2, (CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV)wherein _(jXIV) and _(kXIV) are integers independently selected from 0and 1 with the proviso that, when Z_(XIV) is a covalent single bond, anR_(XIV-15) substituent is not attached to Z_(XIV);

R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members, and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a heterocyclyl having from 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting of acycloalkenyl ring having from 5 through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XIV-5), R_(XIV-6),R_(XIV-7), and R_(XIV-8) present, that there are one to five non-hydridoring substituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-2),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7), R_(XIV-2) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV-4) and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV-6) and R_(XIV-7), and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11),R_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13), R_(XIV-8) andR_(XIV-9), and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

Compounds of Formula XIV are disclosed in WO 00/18721, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIV:

-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methlylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanoi;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)    phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;    and-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

and pharmaceutically acceptable forms thereof, wherein:

n_(XV) is an integer selected from 1 through 2;

A_(XV) and Q_(XV) are independently selected from the group consistingof—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV)—H,

with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 and thatone of A_(XV) and Q_(XV) must be selected from the group consisting ofAQ-2 and—CH₂(CR_(XV-32)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV)—H;

T_(XV) is selected from the group consisting of a single covalent bond,O, S, S(O), S(O)₂, C(R_(XV-33))═C(R_(XV-35)), and C≡C;

_(vXV) is an integer selected from 0 through 1 with the proviso that_(vXV) is 1 when any one of R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

_(uXV) and _(wXV) are integers independently selected from 0 through 6;

A_(XV-1) is C(R_(XV-30));

D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-2) are independentlyselected from the group consisting of C, N, O, S and a covalent bondwith the provisos that no more than one of D_(XV-1), D_(XV-2), J_(XV-1),J_(XV-2), and K_(XV-2) is a covalent bond, no more than one of D_(XV-1),D_(XV-)2, J_(XV-1), J_(XV-2), and K_(XV-1) is O, no more than one ofD_(XV-1), D_(XV-2), J_(XV-)1, J_(XV-2), and K_(XV-1) is S, one ofD_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) must be a covalentbond when two of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1)are O and S, and no more than four of D_(XV-1), D_(XV-2), J_(XV-1),J_(XV-)2, and K_(XV-1) are N;

B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C, C(R_(XV-30)),N, O, S and a covalent bond with the provisos that no more than 5 ofB_(XV-2), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are a covalent bond, no more than two of B_(XV-2), B_(XV-2), D_(XV-3),D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are O, no more than two ofB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-)4, J_(XV-3), J_(XV-)4, and K_(XV-2)are S, no more than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4),J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneously O and S, and no morethan two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4),and K_(XV-2) are N;

B_(XV-2) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) and K_(XV-2),K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) and B_(XV-2)are independently selected to form an in-ring spacer pair wherein saidspacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously C(R_(XV-33))═C(R_(XV-35))and that no more than one of the group of said spacer pairs can be N═Nunless the other spacer pairs are other than C(R_(XV-33))═C(R_(XV-35)),O, N, and S;

R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

R_(XV-2) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

R_(XV-3) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, and haloalkoxyalkyl;

Y_(XV) is selected from the group consisting of a covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

Z_(XV) is selected from the group consisting of covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2, and(C₁₋₁₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

R_(XV-4), R_(XV-8), R_(XV-9) and R_(XV-13) are independently selectedfrom the group consisting of hydrido, halo, haloalkyl, and alkyl;

R_(XV-30) is selected from the group consisting of hydrido, alkoxy,alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl,alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso thatR_(XV-30) is selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring linear spacer connecting the A_(XV-1)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-31), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from 5 through 10 contiguous members;

R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring branched spacer connecting the A_(XV-1)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubstituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12), and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

R_(XV-4), R_(XV-5), R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10),R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33),R_(XV-34), R_(XV-35), and R_(XV-36) are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31) andR_(XV-32) are independently selected to be oxo with the provisos thatB_(XV-1), B_(XV-2), D_(XV-3) D_(XV-4), J_(XV-3), J_(XV-4) and K_(XV-2)are independently selected from the group consisting of C and S, no morethan two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13),R_(XV-31), and R_(XV-32) are simultaneously oxo, and that R_(XV-9),R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), and R_(XV-32) areeach independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6) and R_(XV-7),R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11),R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) andR_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5), R_(XV-5)and R_(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) is used atthe same time and that no more than one of the group consisting ofspacer pairs R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11), R_(XV-11)and R_(XV-31) R_(XV-31) and R_(XV-32), R_(XV-32) and R_(XV-12), andR_(XV-12) and R_(XV-13) are used at the same time;

R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) and R_(XV-13)R_(XV-9) and R_(XV-31), R_(XV-9) and R_(XV-32), R_(XV-10) and R_(XV-12),R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31), R_(XV-10) andR_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-11) and R_(XV-13), R_(XV-11)and R_(XV-32). R_(XV-12) and R_(XV-31), R_(XV-13) and R_(XV-31), andR_(XV-13) and R_(XV-32) are independently selected to form a spacer pairwherein said spacer pair is taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 3 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, a saturated heterocyclyl having from 5 through 8 contiguousmembers and a partially saturated heterocyclyl having from 5 through 8contiguous members with the provisos that no more than one of said groupof spacer pairs is used at the same time;

R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

Compounds of Formula XV are disclosed in WO 00/18723, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XV:

-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol:-   3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)    amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethy)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phennyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl]-(cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluoropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluoropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluoropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluoropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;    and-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols having the Formula XVI

and pharmaceutically acceptable forms thereof, wherein:

n_(XVI) is an integer selected from 1 through 4;

X_(XVI) is oxy;

R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XVI-1) has a higher Cahn-Ingold-Prelog stereochemical systemranking than both R_(XVI-2) and (CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI)wherein A_(XVI) is Formula XVI-(II) and Q is Formula XVI-(III);

R_(XVI-16) is selected from the group consisting of hydrido, alkyl,acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from thegroup consisting of a covalent single bond and a linear spacer moietyhaving a chain length of 1 to 4 atoms linked to the point of bonding ofany aromatic substituent selected from the group consisting ofR_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form a heterocyclylring having from 5 through 10 contiguous members;

D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be 0, no more than one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O and S, and no more than four ofD_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is N;

D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is O, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) is S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is O and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-Ingold-Prelog system ranking than both R_(XVI-1) and(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI);

R_(XVI-3) is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI) has a lower Cahn-Ingold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-Ingold-Prelog stereochemical system ranking than R_(XVI-2);

Y_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-14))₂)_(q) wherein q is an integer selected from 1 and 2 and(CH(R_(XVI-14)))_(g)—W_(XVI)—(CH(R_(XVI-14)))_(p) wherein g and p areintegers independently selected from 0 and 1;

R_(XVI-14) is selected from the group consisting of hydrido, hydroxy,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

Z_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-15))₂)_(q), wherein q is an integer selected from 1 and 2, and(CH(R_(XVI-15)))_(j)—W_(SVI)—(CH(R_(XVI-15))_(k) wherein j and k areintegers independently selected from 0 and 1;

W_(XVI) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)), (R_(XVI-14))NC(O),(R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)),(R_(XVI-14))NS(O)₂, and N(R_(XVI-14)) with the proviso that R_(XVI-14)is other than cyano;

R_(XVI-15) is selected, from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-12), and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), R_(XVI-7) and R_(XVI-8), R_(XVI-9) and R_(XVI-10), R_(XVI-10)and R_(XVI-11), R_(XVI-11) and R_(XVI-12), and R_(XVI-12) and R_(XIV-13)are independently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XIV-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XVI-13) can be used at the same time;

R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), R_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

Compounds of Formula XVI are disclosed in WO 00/18724, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XVI:

-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2,-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]1-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;    and-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of quinolines of Formula XVII

and pharmaceutically acceptable forms thereof, wherein:

A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5), wherein

R_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formula

R_(XVII-6)L_(XVII),

or R_(XVII10)-T_(XVII)-V_(XVII)—X_(XVII)—

wherein

R_(XVII-6), R_(XVII-7), R_(XVII-10) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14)R_(XVII-15);

R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(XVII-14) and R_(XVII-15) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-s) given above, or

R_(XVII-6) and/or R_(XVII-7) denote a radical according to the formula

R_(XVII-8) denotes a hydrogen or halogen, and

R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17);

R_(XVII-16) and R_(XVII-17) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-5) above; or

R_(XVII-8) and R_(XVII-9) together form a radical according to theformula ═O or ═NR_(XVII-18);

R_(XVII-18) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each;

L_(XVII) denotes a straight-chain or branched alkylene or alkenylenechain containing up to 8 carbon atoms each, which are optionallysubstituted with up to two hydroxyl groups;

T_(XVII) and X_(XVII) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

T_(XVII) and X_(XVII) denotes a bond;

V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

R_(XVII-19) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl;

E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl;

R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

R_(XVII-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or

R_(XVII-1) and/or R_(XVII-2) are straight-chain or branched alkyl withup to 6 carbon atoms, optionally substituted with halogen,trifluoromethoxy, hydroxy, or a straight-chain or branched alkoxy withup to 4 carbon atoms, aryl containing 6-10 carbon atoms optionallysubstituted with up to five of the same or different substituentsselected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23);

R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched alkyl up to 6 carbonatoms; and/or

R_(XVII-1) and R_(XVII-2) taken together form a straight-chain orbranched alkene or alkane with up to 6 carbon atoms optionallysubstituted with halogen, trifluoromethyl, hydroxy or straight-chain orbranched alkoxy with up to 5 carbon atoms;

R_(XVII-3) denotes hydrogen, a straight-chain or branched acyl with upto 20 carbon atoms, a benzoyl optionally substituted with halogen,trifluoromethyl, nitro or trifluoromethoxy, a straight-chained orbranched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstituted phenyl, and/or an alkyl that is optionally substituted witha group according to the formula —OR_(XVII-24);

R_(XVII-24) is a straight-chained or branched acyl with up to 4 carbonatoms or benzyl.

Compounds of Formula XVII are disclosed in WO 98/39299, the entiredisclosure is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-Phenyltetrahydroquinolines of Formula XVIII

, N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

A_(XVIII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

D_(XVIII) denotes the formula

or R_(XVIII-8)—CH₂—O—CH₂—;

R_(XVIII-5) and R_(XVIII-6) are taken together to form ═O; or

R_(XVIII-5) denotes hydrogen and R_(XVIII-6) denotes halogen orhydrogen; or

R_(XVIII-5) and R_(XVIII-6) denote hydrogen;

R_(XVIII-7) and R_(XVIII-8) are identical or different and denotephenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl withup to four identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVIII-9)R_(XVIII-10);

R_(XVIII-9) and R_(XVIII-10) are identical or different and denotehydrogen or a straight-chained or branched alkyl of up to three carbonatoms;

E_(XVIII) denotes a cycloalkyl of from three to six carbon atoms or astraight-chained or branched alkyl of up to eight carbon atoms;

R_(XVIII-1) denotes hydroxy;

R_(XVIII-2) denotes hydrogen or methyl;

R_(XVIII-3) and R_(XVIII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

R_(XVIII-3) and R_(XVIII-4) taken together form an alkenylene made up ofbetween two and four carbon atoms.

Compounds of Formula XVIII are disclosed in WO 99/15504, the entiredisclosure of which is incorporated by reference.

Concentration-Enhancing Polymers

Concentration-enhancing polymers suitable for use in the compositions ofthe present invention should be inert, in the sense that they do notchemically react with the CETP inhibitor in an adverse manner, arepharmaceutically acceptable, and have at least some solubility inaqueous solution at physiologically relevant pHs (e.g. 1-8). The polymercan be neutral or ionizable, and should have an aqueous-solubility of atleast 0.1 mg/mL over at least a portion of the pH range of 1-8.

The polymer is a “concentration-enhancing polymer,” meaning that itmeets at least one, and more preferably both, of the followingconditions. The first condition is that the concentration-enhancingpolymer increases the MDC of the CETP inhibitor in the environment ofuse relative to a control composition consisting of an equivalent amountof the CETP inhibitor but no polymer. That is, once the composition isintroduced into an environment of use, the polymer increases the aqueousconcentration of CETP inhibitor relative to the control composition.Preferably, the polymer increases the MDC of the CETP inhibitor inaqueous solution by at least 10-fold relative to a control composition,preferably by at least 50-fold, and more preferably by at least200-fold. Even more preferably, the polymer increases the MDC of theCETP inhibitor in aqueous solution by at least 500-fold, and mostpreferably by at least 1000-fold. Such large enhancements may benecessary in order for some extremely water insoluble CETP inhibitors toachieve effective blood levels through oral dosing. The second conditionis that the concentration-enhancing polymer increases the AUC of theCETP inhibitor in the environment of use relative to a controlcomposition consisting of a CETP inhibitor but no polymer as describedabove. That is, in the environment of use, the composition comprisingthe CETP inhibitor and the concentration-enhancing polymer provides anarea under the concentration versus time curve (AUC) for any period of90 minutes between the time of introduction into the use environment andabout 270 minutes following introduction to the use environment that isat least 5-fold that of a control composition comprising an equivalentquantity of CETP inhibitor but no polymer. Preferably, the AUC providedby the composition is at least 25-fold, more preferably at least100-fold, and even more preferably at least 250-fold that of the controlcomposition.

Concentration-enhancing polymers suitable for use with the presentinvention may be cellulosic or non-cellulosic. The polymers may beneutral or ionizable in aqueous solution. Of these, ionizable andcellulosic polymers are preferred, with ionizable cellulosic polymersbeing more preferred.

A preferred class of polymers comprises polymers that are “amphiphilic”in nature, meaning that the polymer has hydrophobic and hydrophilicportions. The hydrophobic portion may comprise groups such as aliphaticor aromatic hydrocarbon groups. The hydrophilic portion may compriseeither ionizable or non-ionizable groups that are capable of hydrogenbonding such as hydroxyls, carboxylic acids, esters, amines or amides.Amphiphilic and/or ionizable polymers are preferred because it isbelieved that such polymers may tend to have relatively stronginteractions with the CETP inhibitor and may promote the formation ofthe various types of polymer/drug assemblies in the use environment asdescribed previously. In addition, the repulsion of the like charges ofthe ionized groups of such polymers may serve to limit the size of thepolymer/drug assemblies to the nanometer or submicron scale. Forexample, while not wishing to be bound by a particular theory, suchpolymer/drug assemblies may comprise hydrophobic CETP inhibitor clusterssurrounded by the polymer with the polymer's hydrophobic regions turnedinward towards the CETP inhibitor and the hydrophilic regions of thepolymer turned outward toward the aqueous environment. Alternatively,depending on the specific chemical nature of the CETP inhibitor, theionized functional groups of the polymer may associate, for example, viaion pairing or hydrogen bonds, with ionic or polar groups of the CETPinhibitor. In the case of ionizable polymers, the hydrophilic regions ofthe polymer would include the ionized functional groups. Suchpolymer/drug assemblies in solution may well resemble charged polymericmicellar-like structures. In any case, regardless of the mechanism ofaction, the inventors have observed that such amphiphilic polymers,particularly ionizable cellulosic polymers, have been shown to improvethe MDC and/or AUC of CETP inhibitor in aqueous solution relative tocontrol compositions free from such polymers.

Surprisingly, such amphiphilic polymers can greatly enhance the maximumconcentration of CETP inhibitor obtained when CETP inhibitor is dosed toa use environment. In addition, such amphiphilic polymers interact withthe CETP inhibitor to prevent the precipitation or crystallization ofthe CETP inhibitor from solution despite its concentration beingsubstantially above its equilibrium concentration. In particular, whenthe preferred compositions are solid amorphous dispersions of the CETPinhibitor and the concentration-enhancing polymer, the compositionsprovide a greatly enhanced drug concentration, particularly when thedispersions are substantially homogeneous. The maximum drugconcentration may be 10-fold and often more than 50-fold the equilibriumconcentration of the crystalline CETP inhibitor. Indeed, for someextremely water insoluble CETP inhibitors, the maximum drugconcentration may be 200-fold to 500-fold and often more than 1000-foldthe equilibrium concentration of the crystalline CETP inhibitor. Suchenhanced CETP inhibitor concentrations in turn lead to substantiallyenhanced relative bioavailability for the CETP inhibitor.

One class of polymers suitable for use with the present inventioncomprises neutral non-cellulosic polymers.

Exemplary polymers include: vinyl polymers and copolymers havingsubstituents of hydroxyl, alkylacyloxy, or cyclicamido; polyvinylalcohols that have at least a portion of their repeat units in theunhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetatecopolymers; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylenecopolymers, also known as poloxamers; and polyethylene polyvinyl alcoholcopolymers.

Another class of polymers suitable for use with the present inventioncomprises ionizable non-cellulosic polymers. Exemplary polymers include:carboxylic acid-functionalized vinyl polymers, such as the carboxylicacid functionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates such as the EUDRAGITS® manufactured by Rohm Tech Inc., ofMalden, Mass.; amine-functionalized polyacrylates and polymethacrylates;proteins; and carboxylic acid functionalized starches such as starchglycolate. Non-cellulosic polymers that are amphiphilic are copolymersof a relatively hydrophilic and a relatively hydrophobic monomer.Examples include acrylate and methacrylate copolymers, andpolyoxyethylene-polyoxypropylene copolymers. Exemplary commercial gradesof such copolymers include the EUDRAGITS, which are copolymers ofmethacrylates and acrylates, and the PLURONICS supplied by BASF, whichare polyoxyethylene-polyoxypropylene copolymers.

A preferred class of polymers comprises ionizable and neutral cellulosicpolymers with at least one ester- and/or ether-linked substituent inwhich the polymer has a degree of substitution of at least 0.1 for eachsubstituent.

It should be noted that in the polymer nomenclature used herein,ether-linked substituents are recited prior to “cellulose” as the moietyattached to the ether group; for example, “ethylbenzoic acid cellulose”has ethoxybenzoic acid substituents. Analogously, ester-linkedsubstituents are recited after “cellulose” as the carboxylate; forexample, “cellulose phthalate” has one carboxylic acid of each phthalatemoiety ester-linked to the polymer and the other carboxylic acidunreacted.

It should also be noted that a polymer name such as “cellulose acetatephthalate” (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from 0.1 to 2.9 as long as the other criteria of the polymer aremet. “Degree of substitution” refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

Amphiphilic cellulosics comprise polymers in which the parent cellulosicpolymer has been substituted at any or all of the 3 hydroxyl groupspresent on each saccharide repeat unit with at least one relativelyhydrophobic substituent. Hydrophobic substituents may be essentially anysubstituent that, if substituted to a high enough level or degree ofsubstitution, can render the cellulosic polymer essentially aqueousinsoluble. Examples of hydrophobic substitutents include ether-linkedalkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linkedalkyl groups such as acetate, propionate, butyrate, etc.; and ether-and/or ester-linked aryl groups such as phenyl, benzoate, or phenylate.Hydrophilic regions of the polymer can be either those portions that arerelatively unsubstituted, since the unsubstituted hydroxyls arethemselves relatively hydrophilic, or those regions that are substitutedwith hydrophilic substituents. Hydrophilic substituents include ether-or ester-linked nonionizable groups such as the hydroxy alkylsubstituents hydroxyethyl, hydroxypropyl, and the alkyl ether groupssuch as ethoxyethoxy or methoxyethoxy. Particularly preferredhydrophilic substituents are those that are ether- or ester-linkedionizable groups such as carboxylic acids, thiocarboxylic acids,substituted phenoxy groups, amines, phosphates or sulfonates.

One class of cellulosic polymers comprises neutral polymers, meaningthat the polymers are substantially non-ionizable in aqueous solution.Such polymers contain non-ionizable substituents, which may be eitherether-linked or ester-linked. Exemplary ether-linked non-ionizablesubstituents include: alkyl groups, such as methyl, ethyl, propyl,butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.; and aryl groups such as phenyl. Exemplaryester-linked non-ionizable substituents include: alkyl groups, such asacetate, propionate, butyrate, etc.; and aryl groups such as phenylate.However, when aryl groups are included, the polymer may need to includea sufficient amount of a hydrophilic substituent so that the polymer hasat least some water solubility at any physiologically relevant pH offrom 1 to 8.

Exemplary non-ionizable polymers that may be used as the polymerinclude: hydroxypropyl methyl cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose.

A preferred set of neutral cellulosic polymers are those that areamphiphilic. Exemplary polymers include hydroxypropyl methyl celluloseand hydroxypropyl cellulose acetate, where cellulosic repeat units thathave relatively high numbers of methyl or acetate substituents relativeto the unsubstituted hydroxyl or hydroxypropyl substituents constitutehydrophobic regions relative to other repeat units on the polymer.

A preferred class of cellulosic polymers comprises polymers that are atleast partially ionizable at physiologically relevant pH and include atleast one ionizable substituent, which may be either ether-linked orester-linked. Exemplary ether-linked ionizable substituents include:carboxylic acids, such as acetic acid, propionic acid, benzoic acid,salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid orpropoxybenzoic acid, the various isomers of alkoxyphthalic acid such asethoxyphthalic acid and ethoxyisophthalic acid, the various isomers ofalkoxynicotinic acid such as ethoxynicotinic acid, and the variousisomers of picolinic acid such as ethoxypicolinic acid, etc.;thiocarboxylic acids, such as thioacetic acid; substituted phenoxygroups, such as hydroxyphenoxy, etc.; amines, such as aminoethoxy,diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such asphosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplaryester linked ionizable substituents include: carboxylic acids, such assuccinate, citrate, phthalate, terephthalate, isophthalate,trimellitate, and the various isomers of pyridinedicarboxylic acid,etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxygroups, such as amino salicylic acid; amines, such as natural orsynthetic amino acids, such as alanine or phenylalanine; phosphates,such as acetyl phosphate; and sulfonates, such as acetyl sulfonate. Foraromatic-substituted polymers to also have the requisite aqueoussolubility, it is also desirable that sufficient hydrophilic groups suchas hydroxypropyl or carboxylic acid functional groups be attached to thepolymer to render the polymer aqueous soluble at least at pH valueswhere any ionizable groups are ionized. In some cases, the aromaticgroup may itself be ionizable, such as phthalate or trimellitatesubstituents.

Exemplary cellulosic polymers that are at least partially ionized atphysiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethylcellulose, carboxymethyl cellulose, carboxymethylethyl cellulose,cellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, hydroxypropyl methyl celluloseacetate succinate phthalate, hydroxypropyl methyl cellulose succinatephthalate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

Exemplary ionizable cellulosic polymers that meet the definition ofamphiphilic, having hydrophilic and hydrophobic regions, includepolymers such as cellulose acetate phthalate and cellulose acetatetrimellitate where the cellulosic repeat units that have one or moreacetate substituents are hydrophobic relative to those that have noacetate substituents or have one or more ionized phthalate ortrimellitate substituents.

A particularly desirable subset of cellulosic ionizable polymers arethose that possess both a carboxylic acid functional aromaticsubstituent and an alkylate substituent and thus are amphiphilic.Exemplary polymers include cellulose acetate phthalate, methyl celluloseacetate phthalate, ethyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

Another particularly desirable subset of cellulosic ionizable polymersare those that are amphiphilic and possess a non-aromatic carboxylatesubstituent. Exemplary polymers include hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl celluloseacetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethylcellulose acetate succinate, and carboxymethyl ethyl cellulose.

While, as listed above, a wide range of polymers may be used to formdispersions of CETP inhibitors, the inventors have found that relativelyhydrophobic polymers have shown the best performance as demonstrated byhigh MDC and AUC values. In particular, cellulosic polymers that areaqueous insoluble in their nonionized state but are at least sparinglyaqueous soluble in their ionized state perform particularly well. Aparticular subclass of such polymers are the so-called “enteric”polymers which include, for example, certain grades of hydroxypropylmethyl cellulose phthalate and cellulose acetate trimellitate.Dispersions formed from such polymers generally show very largeenhancements, on the order of 50-fold to over 1000-fold, in the maximumdrug concentration achieved in dissolution tests relative to that for acrystalline drug control. In addition, non-enteric grades of suchpolymers as well as closely related cellulosic polymers are expected toperform well due to the similarities in physical properties within theCETP inhibitor class.

Thus, especially preferred polymers are hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate(HPMCP), cellulose acetate phthalate (CAP), cellulose acetatetrimellitate (CAT), methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate celluloseacetate isophthalate, and carboxymethyl ethyl cellulose. The mostpreferred ionizable cellulosic polymers are hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,cellulose acetate phthalate, cellulose acetate trimellitate, andcarboxymethyl ethyl cellulose.

One particularly effective polymer for forming dispersions of thepresent invention is carboxymethyl ethyl cellulose (CMEC). Dispersionsmade from CETP inhibitors and CMEC typically have high glass-transitiontemperatures at high relative humidities, due to the highglass-transition temperature of CMEC. As discussed below, such highT_(g)s result in solid amorphous dispersions with excellent physicalstability. In addition, because all of the substituents on CMEC areattached to the cellulose backbone through ether linkages, CMEC hasexcellent chemical stability. Additionally, commercial grades of CMEC,such as that provided by Freund Industrial Company, Limited (Tokyo,Japan), are amphiphilic, leading to high degrees of concentrationenhancement. Finally, hydrophobic CETP inhibitors often have a highsolubility in CMEC allowing for formation of physically stabledispersions with high drug loadings.

Another preferred class of polymers consists of neutralized acidicpolymers. By “neutralized acidic polymer” is meant any acidic polymerfor which a significant fraction of the “acidic moieties” or “acidicsubstituents” have been “neutralized”; that is, exist in theirdeprotonated form. By “acidic polymer” is meant any polymer thatpossesses a significant number of acidic moieties. In general, asignificant number of acidic moieties would be greater than or equal toabout 0.1 milliequivalents of acidic moieties per gram of polymer.“Acidic moieties” include any functional groups that are sufficientlyacidic that, in contact with or dissolved in water, can at leastpartially donate a hydrogen cation to water and thus increase thehydrogen-ion concentration. This definition includes any functionalgroup or “substituent,” as it is termed when the functional group iscovalently attached to a polymer, that has a pK, of less than about 10.Exemplary classes of functional groups that are included in the abovedescription include carboxylic acids, thiocarboxylic acids, phosphates,phenolic groups, and sulfonates. Such functional groups may make up theprimary structure of the polymer such as for polyacrylic acid, but moregenerally are covalently attached to the backbone of the parent polymerand thus are termed “substituents.”

The “degree of neutralization,” α, of a polymer substituted withmonoprotic acids (such as carboxylic acids) is defined as the fractionof the acidic moieties on the polymer that have been neutralized; thatis, deprotonated by a base. Typically, for an acidic polymer to beconsidered a “neutralized acidic polymer,” α must be at least about0.001 (or 0.1%), preferably about 0.01 (1%) and more preferably at leastabout 0.1 (10%). Such small degrees of neutralization may be acceptablebecause often the effective pH of the polymer changes dramatically withsmall increases in the degree of neutralization. Nonetheless, evengreater degrees of neutralization are even more preferred. Thus, α ispreferably at least 0.5 (meaning that at least 50% of the acidicmoieties have been neutralized) and α is more preferably at least 0.9(meaning that at least 90% of the acidic moieties have beenneutralized).

Neutralized acidic polymers are described in more detail in commonlyassigned pending U.S. provisional patent application Ser. No. 60/300,256entitled “Pharmaceutical Compositions of Drugs and Neutralized AcidicPolymers” filed Jun. 22, 2001, the relevant disclosure of which isincorporated by reference.

When the neutralized form of the acidic polymer comprises a multivalentcationic species such as Ca²⁺, Mg²⁺, A³⁺, Fe²⁺, Fe³⁺, or a diamine, suchas ethylene diamine, the cationic species may interact with two or moreneutralized acidic moieties on more than one polymer chain, resulting inan ionic crosslink between the polymer chains. An acidic polymer may beconsidered “ionically crosslinked” if the number of milliequivalents ofmultivalent cationic species per gram of polymer is at least 5%,preferably at least 10% the number of milliequivalents of acidicmoieties (of the polymer) per gram of polymer. Alternatively, an acidicpolymer may be considered “ionically crosslinked” if sufficientmultivalent cationic species are present such that the neutralizedacidic polymer has a higher T_(g) than the same polymer containingessentially no multivalent cationic species. Drug mobility indispersions formed from such ionically crosslinked polymers isparticularly low relative to dispersions formed from the acidic form ofthe same polymers. Such ionically crosslinked polymers may be formed byneutralization of the acidic polymer using any base where the cationiccounterion of the base is divalent. Thus, calcium hydroxide, magnesiumacetate or ethylene diamine may be added to an acidic polymer such ascellulosic acetate phthalate or hydroxypropyl methyl cellulose acetatesuccinate to form a neutralized, ionically crosslinked, acidiccellulosic polymer. Low drug mobility in such polymers may be indicatedby high T_(g) values or, more typically, a decrease in the magnitude ofthe heat capacity increase in the vicinity of the T_(g) or, in somecases, the absence of any apparent T_(g) when the dispersion issubjected to differential thermal analysis. Thus, when the polymer isessentially completely neutralized, no T_(g) is apparent when theneutralized polymer is subjected to differential thermal analysis. Suchionically cross-linked polymers may provide improved physical stabilityfor the drug in the dispersion relative to non-ionically crosslinkedneutralized acidic polymer.

While specific polymers have been discussed as being suitable for use inthe compositions of the present invention, blends of such polymers mayalso be suitable. Thus the term “polymer” is intended to include blendsof polymers in addition to a single species of polymer.

To obtain the best performance, particularly upon storage for long timesprior to use, it is preferred that the CETP inhibitor remain, to theextent possible, in the amorphous state. The inventors have found thatthis may best be achieved by two distinct methods. In the first method,the glass-transition temperature, T_(g), of the amorphous CETP inhibitormaterial is substantially above the storage temperature of thecomposition. In particular, it is preferable that the T_(g) of theamorphous state of the CETP inhibitor be at least 40° C. and preferablyat least 60° C. For those aspects of the invention in which thecomposition is a solid, substantially amorphous dispersion of CETPinhibitor in the concentration-enhancing polymer and in which the CETPinhibitor itself has a relatively low T_(g) (about 70° C. or less) it ispreferred that the concentration-enhancing polymer have a T_(g) of atleast 40° C., preferably at least 70° C. and more preferably greaterthan 100° C. Exemplary high T_(g) polymers include HPMCAS, HPMCP, CAP,CAT, CMEC and other cellulosics that have alkylate or aromaticsubstituents or both alkylate and aromatic substituents.

In a second method, the concentration-enhancing polymer is chosen suchthat the amorphous CETP inhibitor is highly soluble in theconcentration-enhancing polymer. In general, the concentration-enhancingpolymer and CETP inhibitor concentration are chosen such that thesolubility of the CETP inhibitor is roughly equal to or greater than theconcentration of CETP inhibitor in the concentration-enhancing polymer.It is often preferred that the CETP inhibitor composition be chosen suchthat both methods—high T_(g) and high solubility—are satisfied.

In addition, the preferred polymers listed above, that is amphiphiliccellulosic polymers, tend to have greater concentration-enhancingproperties relative to the other polymers of the present invention. Forany particular CETP inhibitor, the amphiphilic cellulosic with the bestconcentration-enhancing properties may vary. However, the inventors havefound that generally those that have ionizable substituents as well ashydrophobic substituents such as methoxy, ethoxy and acetate tend toperform best. In vitro tests of compositions with such polymers tend tohave higher MDC and AUC values than compositions with other polymers ofthe invention.

Preparation of Compositions

Dispersions of the CETP inhibitor and concentration-enhancing polymermay be made according to any known process which results in at least amajor portion (at least 60%) of the CETP inhibitor being in theamorphous state. Exemplary mechanical processes include milling andextrusion; melt processes include high temperature fusion, solventmodified fusion and melt-congeal processes; and solvent processesinclude non-solvent precipitation, spray coating and spray-drying. See,for example, U.S. Pat. No. 5,456,923, U.S. Pat. No. 5,939,099 and U.S.Pat. No. 4,801,460 which describe formation of dispersions via extrusionprocesses; U.S. Pat. No. 5,340,591 and U.S. Pat. No. 4,673,564 whichdescribe forming dispersions by milling processes; and U.S. Pat. No.5,684,040, U.S. Pat. No. 4,894,235 and U.S. Pat. No. 5,707,646 whichdescribe the formation of dispersions via melt/congeal processes, thedisclosures of which are incorporated by reference. Although thedispersions of the present invention may be made by any of theseprocesses, the dispersions generally have their maximum bioavailabilityand stability when the CETP inhibitor is dispersed in the polymer suchthat it is substantially amorphous and substantially homogeneouslydistributed throughout the polymer.

In general, as the degree of homogeneity of the dispersion increases,the enhancement in the aqueous concentration of the CETP inhibitor andrelative bioavailability increases as well. Given the extremely lowaqueous solubility and bioavailability of many CETP inhibitors, it isoften highly preferred for the dispersions to be as homogeneous aspossible to achieve therapeutically effective levels of CETP inhibitors.Thus, most preferred are dispersions having a single glass transitiontemperature, which indicates a high degree of homogeneity. Dispersionswith more than one T_(g), indicating at least partial amorphous phaseseparation, may also function well, particularly when neither amorphousphase is comprised only of amorphous drug, but rather also contains asignificant amount of concentration-enhancing polymer.

In one embodiment, the solid amorphous dispersion of CETP inhibitor andconcentration-enhancing polymer may be formed via a melt-congeal ormelt-extrusion process. Such processes are particularly suitable whenthe CETP inhibitor has a relatively low melting point, typically lessthan about 200° C. and preferably less than about 150° C. In suchprocesses, a molten mixture comprising the CETP inhibitor andconcentration-enhancing polymer is rapidly cooled such that the moltenmixture solidifies to form a solid amorphous dispersion. By “moltenmixture” is meant that the mixture comprising the CETP inhibitor andconcentration-enhancing polymer is heated sufficiently that it becomessufficiently fluid that the drug substantially disperses in one or moreof the concentration-enhancing polymer and other excipients. Generally,this requires that the mixture be heated to about 10° C. or more abovethe lower of the melting point of the lowest melting point component inthe composition and the melting point of the drug. The CETP inhibitorcan exist in the molten mixture as a pure phase, as a solution of CETPinhibitor homogeneously distributed throughout the molten mixture, orany combination of these states or those states that lie intermediatebetween them. The molten mixture is preferably substantially homogeneousso that the CETP inhibitor is dispersed as homogeneously as possiblethroughout the molten mixture. When the temperature of the moltenmixture is below the melting point of both the CETP inhibitor and theconcentration-enhancing polymer, the molten excipients,concentration-enhancing polymer, and CETP inhibitor are preferablysufficiently soluble in each other that a substantial portion of theCETP inhibitor disperses in the concentration-enhancing polymer orexcipients. It is often preferred that the mixture be heated above thelower of the melting point of the concentration-enhancing polymer andthe CETP inhibitor.

Generally, the processing temperature may vary from 50° C. up to about200° C. or higher, depending on the melting point of the CETP inhibitorand polymer, which is a function of the polymer grade selected. However,the processing temperature should not be so high that an unacceptablyhigh level of degradation of the drug or polymer occurs. In some cases,the molten mixture should be formed under an inert atmosphere to preventdegradation of the drug and/or polymer at the processing temperature.When relatively high temperatures are used, it is often preferable tominimize the time that the mixture is at the elevated temperature tominimize degradation.

The molten mixture may also comprise an excipient that will reduce themelting temperature of the composition (either the drug and/or thepolymer), allowing processing at lower temperature. When such excipientshave low volatility and substantially remain in the mixture uponsolidification, they generally can comprise up to 30 wt % of the moltenmixture. For example, a plasticizer may be added to the composition toreduce the melting temperature of the polymer. Examples of plasticizersinclude water, triethylcitrate, triacetin, and dibutyl sebacate.Volatile agents that dissolve or swell the polymer, such as acetone,water, methanol, and ethyl acetate, may also be added in low quantitiesto reduce the melting point of the composition. When such volatileexcipients are added, at least a portion, up to essentially all, of suchexcipients may evaporate in the process of or following conversion ofthe molten mixture to a solid mixture. In such cases, the processing maybe considered to be a combination of solvent processing andmelt-congealing or melt-extrusion. Removal of such volatile excipientsfrom the molten mixture can be accomplished by breaking up or atomizingthe molten mixture into small droplets and contacting the droplets witha fluid such that the droplets both cool and lose all or part of thevolatile excipient. Examples of other excipients that can be added tothe composition to reduce the processing temperature include lowmolecular weight polymers or oligomers, such as polyethylene glycol,polyvinylpyrrolidone, and poloxamers; fats and oils, including mono-,di-, and triglycerides; natural and synthetic waxes, such as carnaubawax, beeswax, microcrystalline wax, castor wax, and paraffin wax;long-chain alcohols, such as cetyl alcohol and stearyl alcohol; andlong-chain fatty acids, such as stearic acid. As mentioned above, whenthe excipient added is volatile, it may be removed from the mixturewhile still molten or following solidification to form the solidamorphous dispersion.

Virtually any process may be used to form the molten mixture. One methodinvolves melting the concentration-enhancing polymer in a vessel andthen adding the CETP inhibitor to the molten polymer. Another methodinvolves melting the CETP inhibitor in a vessel and then adding theconcentration-enhancing polymer. In yet another method, a solid blend ofthe CETP inhibitor and concentration-enhancing polymer may be added to avessel and the blend heated to form the molten mixture.

Once the molten mixture is formed, it may be mixed to ensure the CETPinhibitor is homogeneously distributed throughout the molten mixture.Such mixing may be done using mechanical means, such as overhead mixers,magnetically driven mixers and stir bars, planetary mixers, andhomogenizers. Optionally, when the molten mixture is formed in a vessel,the contents of the vessel can be pumped out of the vessel and throughan in-line or static mixer and then returned to the vessel. The amountof shear used to mix the molten mixture should be sufficiently high toensure uniform distribution of the drug in the molten mixture. Themolten mixture can be mixed from a few minutes to several hours, themixing time being dependent on the viscosity of the mixture and thesolubility of the drug and any optional excipients in theconcentration-enhancing polymer.

An alternative method of preparing the molten mixture is to use twovessels, melting the CETP inhibitor in the first vessel and theconcentration-enhancing polymer in a second vessel. The two melts arethen pumped through an in-line static mixer or extruder to produce themolten mixture that is then rapidly solidified.

Alternatively, the molten mixture can be generated using an extruder,such as a single-screw or twin-screw extruder, both well known in theart. In such devices, a solid feed of the composition is fed to theextruder whereby the combination of heat and shear forces produce auniformly mixed molten mixture, which can then be rapidly solidified toform the solid amorphous dispersion. The solid feed can be preparedusing methods well known in the art for obtaining solid mixtures withhigh content uniformity. Alternatively, the extruder may be equippedwith two feeders, allowing the CETP inhibitor to be fed to the extruderthrough one feeder and the polymer through the other. Other excipientsto reduce the processing temperature as described above may be includedin the solid feed, or in the case of liquid excipients, such as water,may be injected into the extruder using methods well-known in the art.

The extruder should be designed such that it produces a molten mixturewith the drug uniformly distributed throughout the composition. Thevarious zones in the extruder should be heated to appropriatetemperatures to obtain the desired extrudate temperature as well as thedesired degree of mixing or shear, using procedures well known in theart.

When the drug has a high solubility in the concentration-enhancingpolymer, a lower amount of mechanical energy will be required to formthe dispersion. In such cases, when the melting point of the undispersedCETP inhibitor is greater than the melting point of the undispersedconcentration-enhancing polymer, the processing temperature may be belowthe melting temperature of the undispersed CETP inhibitor but greaterthan the melting point of the polymer, since the CETP inhibitor willdissolve into the molten polymer. When the melting point of theundispersed CETP inhibitor is less than the melting point of theundispersed concentration-enhancing polymer, the processing temperaturemay be above the melting point of the undispersed CETP inhibitor butbelow the melting point of the undispersed concentration-enhancingpolymer since the molten CETP inhibitor will dissolve in the polymer orbe absorbed into the polymer.

When the CETP inhibitor has a low solubility in the polymer, a higheramount of mechanical energy may be required to form the dispersion.Here, the processing temperature may need to be above the melting pointof the CETP inhibitor and the polymer. As mentioned above,alternatively, a liquid or low-melting point excipient may be added thatpromotes melting or the mutual solubility of the concentration-enhancingpolymer and CETP inhibitor. A high amount of mechanical energy may alsobe needed to mix the CETP inhibitor and the polymer to form adispersion. Typically, the lowest processing temperature and an extruderdesign that imparts the lowest amount of mechanical energy (e.g., shear)that produces a satisfactory dispersion (substantially amorphous andsubstantially homogeneous) is chosen in order to minimize the exposureof the CETP inhibitor to harsh conditions.

Once the molten mixture of CETP inhibitor and concentration-enhancingpolymer is formed, the mixture should be rapidly solidified to form thesolid amorphous dispersion. By “rapidly solidified” is meant that themolten mixture is solidified sufficiently fast such that substantialphase separation of the drug and polymer does not occur. Typically, thismeans that the mixture should be solidified in less than about 10minutes, preferably less than about 5 minutes, more preferably less thanabout 1 minute. If the mixture is not rapidly solidified, phaseseparation can occur, resulting in the formation of CETP inhibitor-richphases and polymer-rich phases. Over time, the drug in the CETPinhibitor-rich phases can crystallize. Such compositions are thereforenot substantially amorphous or substantially homogeneous and tend not toperform as well as those compositions that are rapidly solidified andare substantially amorphous and substantially homogeneous.Solidification often takes place primarily by cooling the molten mixtureto at least about 10° C. and preferably at least about 30° C. below itsmelting point. As mentioned above, solidification can be additionallypromoted by evaporation of all or part of one or more volatileexcipients or solvents. To promote rapid cooling and evaporation ofvolatile excipients, the molten mixture is often formed into a highsurface area shape such as a rod or fiber or droplets. For example, themolten mixture can be forced through one or more small holes to formlong thin fibers or rods or may be fed to a device, such as an atomizersuch as a rotating disk, that breaks the molten mixture up into dropletsfrom 1 μm to 1 cm in diameter. The droplets are then contacted with arelatively cool fluid such as air or nitrogen to promote cooling andevaporation.

A useful tool for evaluating and selecting conditions for formingsubstantially homogeneous, substantially amorphous dispersions via amelt-congeal or extrusion process is the differential scanningcalorimeter (DSC). While the rate at which samples can be heated andcooled in a DSC is limited, it does allow for precise control of thethermal history of a sample. For example, the CETP inhibitor andconcentration-enhancing polymer may be dry blended and then placed intothe DSC sample pan. The DSC can then be programmed to heat the sample atthe desired rate, hold the sample at the desired temperature for adesired time, and then rapidly cool the sample to ambient or lowertemperature. The sample can then be re-analyzed on the DSC to verify thesample was transformed into a substantially homogeneous, substantiallyamorphous dispersion (e.g., the sample has a single Tg). Using thisprocedure, the temperature and time required to achieve a substantiallyhomogeneous, substantially amorphous dispersion for a given CETPinhibitor and concentration-enhancing polymer can be determined.

Another method for forming substantially amorphous and substantiallyhomogeneous dispersions is by “solvent processing,” which consists ofdissolution of the CETP inhibitor and one or more polymers in a commonsolvent. “Common” here means that the solvent, which can be a mixture ofcompounds, will simultaneously dissolve the drug and the polymer(s).After both the CETP inhibitor and the polymer have been dissolved, thesolvent is rapidly removed by evaporation or by mixing with anon-solvent. Exemplary processes are spray-drying, spray-coating(pan-coating, fluidized bed coating, etc.), and precipitation by rapidmixing of the polymer and drug solution with CO₂, water, or some othernon-solvent. Preferably, removal of the solvent results in a soliddispersion which is substantially homogeneous. As described previously,in such substantially homogeneous dispersions, the CETP inhibitor isdispersed as homogeneously as possible throughout the polymer and can bethought of as a solid solution of CETP inhibitor dispersed in thepolymer(s). When the resulting dispersion constitutes a solid solutionof CETP inhibitor in polymer, the dispersion may be thermodynamicallystable, meaning that the concentration of CETP inhibitor in the polymeris at or below its equilibrium value, or it may be considered asupersaturated solid solution where the CETP inhibitor concentration inthe dispersion polymer(s) is above its equilibrium value.

The solvent may be removed through the process of spray-drying. The termspray-drying is used conventionally and broadly refers to processesinvolving breaking up liquid mixtures into small droplets (atomization)and rapidly removing solvent from the mixture in a container(spray-drying apparatus) where there is a strong driving force forevaporation of solvent from the droplets. The strong driving force forsolvent evaporation is generally provided by maintaining the partialpressure of solvent in the spray-drying apparatus well below the vaporpressure of the solvent at the temperature of the drying droplets. Thisis accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

Solvents suitable for spray-drying can be any organic compound in whichthe CETP inhibitor and polymer are mutually soluble. Preferably, thesolvent is also volatile with a boiling point of 150° C. or less. Inaddition, the solvent should have relatively low toxicity and be removedfrom the dispersion to a level that is acceptable according to TheInternational Committee on Harmonization (ICH) guidelines. Removal ofsolvent to this level may require a processing step such as tray-dryingsubsequent to the spray-drying or spray-coating process. Preferredsolvents include alcohols such as methanol, ethanol, n-propanol,iso-propanol, and butanol; ketones such as acetone, methyl ethyl ketoneand methyl iso-butyl ketone; esters such as ethyl acetate andpropylacetate; and various other solvents such as acetonitrile,methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatilitysolvents such as dimethyl acetamide or dimethylsulfoxide can also beused. Mixtures of solvents, such as 50% methanol and 50% acetone, canalso be used, as can mixtures with water as long as the polymer and CETPinhibitor are sufficiently soluble to make the spray-drying processpracticable. Generally, due to the hydrophobic nature of CETPinhibitors, non-aqueous solvents are preferred meaning that the solventcomprises less than about 10 wt % water, and preferably less than 1 wt %water.

Generally, the temperature and flow rate of the drying gas is chosen sothat the polymer/drug-solution droplets are dry enough by the time theyreach the wall of the apparatus that they are essentially solid, and sothat they form a fine powder and do not stick to the apparatus wall. Theactual length of time to achieve this level of dryness depends on thesize of the droplets. Droplet sizes generally range from 1 μm to 500 μmin diameter, with 5 μm to 100 μm being more typical. The largesurface-to-volume ratio of the droplets and the large driving force forevaporation of solvent leads to actual drying times of a few seconds orless, and more typically less than 0.1 second. This rapid drying isoften critical to the particles maintaining a uniform, homogeneousdispersion instead of separating into drug-rich and polymer-rich phases.As above, to get large enhancements in concentration and bioavailabilityit is often necessary to obtain as homogeneous of a dispersion aspossible. Solidification times should be less than 100 seconds,preferably less than a few seconds, and more preferably less than 1second. In general, to achieve this rapid solidification of the CETPinhibitor/polymer solution, it is preferred that the size of dropletsformed during the spray-drying process are less than about 100 μm indiameter. The resultant solid particles thus formed are generally lessthan about 100 μm in diameter.

Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of CETP inhibitor molecules in the dispersion, therebyimproving its stability. Generally, the solvent content of thedispersion as it leaves the spray-drying chamber should be less than 10wt % and preferably less than 2 wt %. In some cases, it may bepreferable to spray a solvent or a solution of a polymer or otherexcipient into the spray-drying chamber to form granules, so long as thedispersion is not adversely affected.

Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem. Eng. Prog. Monogr. Series 2 (1954).

The amount of concentration-enhancing polymer relative to the amount ofCETP inhibitor present in the dispersions of the present inventiondepends on the CETP inhibitor and polymer and may vary widely from aCETP inhibitor-to-polymer weight ratio of from 0.01 to about 4 (e.g., 1wt % CETP inhibitor to 80 wt % CETP inhibitor). However, in most casesit is preferred that the CETP inhibitor-to-polymer ratio is greater thanabout 0.05 (4.8 wt % CETP inhibitor) and less than about 2.5 (71 wt %CETP inhibitor). Often the enhancement in CETP inhibitor concentrationor relative bioavailability that is observed increases as the CETPinhibitor-to-polymer ratio decreases from a value of about 1 (50 wt %CETP inhibitor) to a value of about 0.11 (10 wt % CETP inhibitor). Insome cases it has been found that the bioavailability of dispersionswith a CETP-inhibitor-to-polymer ratio of about 0.33 (25 wt % CETPinhibitor) have higher bioavailability when dosed orally thandispersions with a CETP-inhibitor-to-polymer ratio of 0.11 (10 wt % CETPinhibitor). The CETP inhibitor:polymer ratio that yields optimum resultsvaries from CETP inhibitor to CETP inhibitor and is best determined inin vitro dissolution tests and/or in vivo bioavailability tests.

In addition, the amount of concentration-enhancing polymer that can beused in a dosage form is often limited by the total mass requirements ofthe dosage form. For example, when oral dosing to a human is desired, atlow CETP inhibitor-to-polymer ratios the total mass of drug and polymermay be unacceptably large for delivery of the desired dose in a singletablet or capsule. Thus, it is often necessary to use CETPinhibitor-to-polymer ratios that are less than optimum in specificdosage forms to provide a sufficient CETP inhibitor dose in a dosageform that is small enough to be easily delivered to a use environment.

Excipients and Dosage Forms

Although the key ingredients present in the compositions of the presentinvention are simply the CETP inhibitor to be delivered and theconcentration-enhancing polymer(s), the inclusion of other excipients inthe composition may be useful. These excipients may be utilized with theCETP inhibitor and polymer composition in order to formulate thecomposition into tablets, capsules, suspensions, powders for suspension,creams, transdermal patches, depots, and the like. The composition ofCETP inhibitor and polymer can be added to other dosage form ingredientsin essentially any manner that does not substantially alter the CETPinhibitor. The excipients may be either physically mixed with thedispersion and/or included within the dispersion.

One very useful class of excipients is surfactants. Suitable surfactantsinclude fatty acid and alkyl sulfonates; commercial surfactants such asbenzalkonium chloride (HYAMINE® 1622, available from Lonza, Inc.,Fairlawn, N.J.); dioctyl sodium sulfosuccinate, DOCUSATE SODIUM®(available from Mallinckrodt Spec. Chem., St. Louis, Mo.);

polyoxyethylene sorbitan fatty acid esters (TWEEN®, available from ICIAmericas Inc., Wilmington, Del.; LIPOSORB® P-20 available from LipochemInc., Patterson N.J.; CAPMUL® POE-0 available from Abitec Corp.,Janesville, Wis.), and natural surfactants such as sodium taurocholicacid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, andother phospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum dissolvedconcentration, and also to inhibit crystallization or precipitation ofdrug by interacting with the dissolved drug by mechanisms such ascomplexation, formation of inclusion complexes, formation of micelles oradsorbing to the surface of solid drug, crystalline or amorphous. Thesesurfactants may comprise up to 5 wt % of the composition.

The addition of pH modifiers such as acids, bases, or buffers may alsobe beneficial, retarding the dissolution of the composition (e.g., acidssuch as citric acid or succinic acid when the concentration-enhancingpolymer is anionic) or, alternatively, enhancing the rate of dissolutionof the composition (e.g., bases such as sodium acetate or amines whenthe polymer is anionic).

Conventional matrix materials, complexing agents, solubilizers, fillers,disintegrating agents (disintegrants), or binders may also be added aspart of the composition itself or added by granulation via wet ormechanical or other means. These materials may comprise up to 90 wt % ofthe composition.

Examples of matrix materials, fillers, or diluents include lactose,mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, andstarch.

Examples of disintegrants include sodium starch glycolate, sodiumalginate, carboxy methyl cellulose sodium, methyl cellulose, andcroscarmellose sodium.

Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth.

Examples of lubricants include magnesium stearate and calcium stearate.

Other conventional excipients may be employed in the compositions ofthis invention, including those excipients well-known in the art.Generally, excipients such as pigments, lubricants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions. These excipientsmay be utilized in order to formulate the composition into tablets,capsules, suspensions, powders for suspension, creams, transdermalpatches, and the like.

The compositions of the present invention may be delivered by a widevariety of routes, including, but not limited to, oral, nasal, rectal,and pulmonary. Generally, the oral route is preferred.

Compositions of this invention may also be used in a wide variety ofdosage forms for administration of CETP inhibitors. Exemplary dosageforms are powders or granules that may be taken orally either dry orreconstituted by addition of water or other liquids to form a paste,slurry, suspension or solution; tablets; capsules; multiparticulates;and pills. Various additives may be mixed, ground, or granulated withthe compositions of this invention to form a material suitable for theabove dosage forms.

The compositions of the present invention may be formulated in variousforms such that they are delivered as a suspension of particles in aliquid vehicle. Such suspensions may be formulated as a liquid or pasteat the time of manufacture, or they may be formulated as a dry powderwith a liquid, typically water, added at a later time but prior to oraladministration. Such powders that are constituted into a suspension areoften termed sachets or oral powder for constitution (OPC) formulations.Such dosage forms can be formulated and reconstituted via any knownprocedure. The simplest approach is to formulate the dosage form as adry powder that is reconstituted by simply adding water and agitating.Alternatively, the dosage form may be formulated as a liquid and a drypowder that are combined and agitated to form the oral suspension. Inyet another embodiment, the dosage form can be formulated as two powderswhich are reconstituted by first adding water to one powder to form asolution to which the second powder is combined with agitation to formthe suspension.

Generally, it is preferred that the dispersion of CETP inhibitor beformulated for long-term storage in the dry state as this promotes thechemical and physical stability of the CETP inhibitor. Variousexcipients and additives are combined with the compositions of thepresent invention to form the dosage form. For example, it may bedesirable to add some or all of the following: preservatives such assulfites (an antioxidant), benzalkonium chloride, methyl paraben, propylparaben, benzyl alcohol or sodium benzoate; suspending agents orthickeners such as xanthan gum, starch, guar gum, sodium alginate,carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, polyacrylic acid, silica gel,aluminum silicate, magnesium silicate, or titanium dioxide; anticakingagents or fillers such as silicon oxide, or lactose; flavorants such asnatural or artificial flavors; sweeteners such as sugars such assucrose, lactose, or sorbitol as well as artificial sweeteners such asaspartame or saccharin; wetting agents or surfactants such as variousgrades of polysorbate, docusate sodium, or sodium lauryl sulfate;solubilizers such as ethanol propylene glycol or polyethylene glycol;coloring agents such as FD and C Red No. 3 or FD and C Blue No. 1; andpH modifiers or buffers such as carboxylic acids (including citric acid,ascorbic acid, lactic acid, and succinic acid), various salts ofcarboxylic acids, amino acids such as glycine or alanine, variousphosphate, sulfate and carbonate salts such as trisodium phosphate,sodium bicarbonate or potassium bisulfate, and bases such as aminoglucose or triethanol amine.

A preferred additive to such formulations is additionalconcentration-enhancing polymer which may act as a thickener orsuspending agent as well as to enhance the concentration of CETPinhibitor in the environment of use and may also act to prevent orretard precipitation or crystallization of CETP inhibitor from solution.Such preferred additives are hydroxyethyl cellulose, hydroxypropylcellulose, and hydroxypropyl methyl cellulose. In particular, the saltsof carboxylic acid functional polymers such as cellulose acetatephthalate, hydroxypropyl methyl cellulose acetate succinate, andcarboxymethyl cellulose are useful in this regard. Such polymers may beadded in their salt forms or the salt form may be formed in situ duringreconstitution by adding a base such as trisodium phosphate and the acidform of such polymers.

In some cases, the overall dosage form or particles, granules or beadsthat make up the dosage form may have superior performance if coatedwith an enteric polymer to prevent or retard dissolution until thedosage form leaves the stomach. Exemplary enteric coating materialsinclude hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, carboxylic acid-functionalized polymethacrylates,and carboxylic acid-functionalized polyacrylate.

Compositions of this invention may be administered in a controlledrelease dosage form. In one such dosage form, the composition of theCETP inhibitor and polymer is incorporated into an erodible polymericmatrix device. By an erodible matrix is meant aqueous-erodible orwater-swellable or aqueous-soluble in the sense of being either erodibleor swellable or dissolvable in pure water or requiring the presence ofan acid or base to ionize the polymeric matrix sufficiently to causeerosion or dissolution. When contacted with the aqueous environment ofuse, the erodible polymeric matrix imbibes water and forms anaqueous-swollen gel or “matrix” that entraps the dispersion of CETPinhibitor and polymer. The aqueous-swollen matrix gradually erodes,swells, disintegrates or dissolves in the environment of use, therebycontrolling the release of the dispersion to the environment of use.Examples of such dosage forms are disclosed more fully in commonlyassigned pending U.S. patent application Ser. No. 09/495,059 filed Jan.31, 2000 which claimed the benefit of priority of provisional patentapplication Ser. No. 60/119,400 filed Feb. 10, 1999, the relevantdisclosure of which is herein incorporated by reference.

Alternatively, the compositions of the present invention may beadministered by or incorporated into a non-erodible matrix device.

Alternatively, the compositions of the invention may be delivered usinga coated osmotic controlled release dosage form. This dosage form hastwo components: (a) the core which contains an osmotic agent and thedispersion of CETP inhibitor and concentration-enhancing polymer; and(b) a non-dissolving and non-eroding coating surrounding the core, thecoating controlling the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion of some orall of the core to the environment of use. The osmotic agent containedin the core of this device may be an aqueous-swellable hydrophilicpolymer, osmogen, or osmagent. The coating is preferably polymeric,aqueous-permeable, and has at least one delivery port. Examples of suchdosage forms are disclosed more fully in commonly assigned pending U.S.patent application Ser. No. 09/495,061 filed Jan. 31, 2000 which claimedthe benefit of priority of provisional Patent Application Ser. No.60/119,406 filed Feb. 10, 1999, the relevant disclosure of which isherein incorporated by reference.

Alternatively, the compositions may be delivered via a coated hydrogelcontrolled release form having at least two components: (a) a corecomprising the dispersion of the present invention and a hydrogel, and(b) a coating through which the dispersion has passage when the dosageform is exposed to a use environment. Examples of such dosage forms aremore fully disclosed in commonly assigned European Patent EP0378404, therelevant disclosure of which is herein incorporated by reference.

Alternatively, the drug mixture of the invention may be delivered via acoated hydrogel controlled release dosage form having at least threecomponents: (a) a composition containing the dispersion, (b) awater-swellable composition wherein the water-swellable composition isin a separate region within a core formed by the drug-containingcomposition and the water-swellable composition, and (c) a coatingaround the core that is water-permeable, water-insoluble, and has atleast one delivery port therethrough. In use, the core imbibes waterthrough the coating, swelling the water-swellable composition andincreasing the pressure within the core, and fluidizing thedispersion-containing composition. Because the coating remains intact,the dispersion-containing composition is extruded out of the deliveryport into an environment of use. Examples of such dosage forms are morefully disclosed in commonly assigned pending U.S. patent applicationSer. No. 09/745,095, filed Dec. 20, 2000, which claims priority toProvisional Application Ser. No. 60/171,968 filed Dec. 23, 1999, therelevant disclosure of which is herein incorporated by reference.

Alternatively, the compositions may be administered asmultiparticulates. Multiparticulates generally refer to dosage formsthat comprise a multiplicity of particles that may range in size fromabout 10 μm to about 2 mm, more typically about 100 μm to 1 mm indiameter. Such multiparticulates may be packaged, for example, in acapsule such as a gelatin capsule or a capsule formed from anaqueous-soluble polymer such as HPMCAS, HPMC or starch or they may bedosed as a suspension or slurry in a liquid.

Such multiparticulates may be made by any known process, such as wet-and dry-granulation processes, extrusion/spheronization,roller-compaction, or by spray-coating seed cores. For example, in wet-and dry-granulation processes, the composition of CETP inhibitor andconcentration-enhancing polymer is prepared as described above. Thiscomposition is then granulated to form multiparticulates of the desiredsize. Other excipients, such as a binder (e.g., microcrystallinecellulose), may be blended with the composition to aid in processing andforming the multiparticulates. In the case of wet granulation, a bindersuch as microcrystalline cellulose may be included in the granulationfluid to aid in forming a suitable multiparticulate.

In any case, the resulting particles may themselves constitute themultiparticulate dosage form or they may be coated by variousfilm-forming materials such as enteric polymers or water-swellable orwater-soluble polymers, or they may be combined with other excipients orvehicles to aid in dosing to patients.

Compositions of the present invention may be used to treat any conditionwhich is subject to treatment by administering a CETP inhibitor.

One aspect of this invention is directed to a method for treatingatherosclerosis in a mammal (including a human being) by administeringto a mammal in need of such treatment an atherosclerotic treating amountof a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating peripheral vascular disease in a mammal (including a humanbeing) by administering to a mammal in need of such treatment aperipheral vascular disease treating amount of a composition of thepresent invention.

Yet another aspect of this invention is directed to a method fortreating dyslipidemia in a mammal (including a human being) byadministering to a mammal in need of such treatment a dyslipidemiatreating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating hyperbetalipoproteinemia in a mammal (including a human being)by administering to a mammal in need of such treatment ahyperbetalipoproteinemia treating amount of a composition of the presentinvention.

Yet another aspect of this invention is directed to a method fortreating hypoalphalipoproteinemia in a mammal (including a human being)by administering to a mammal in need of such treatment ahypoalphalipoproteinemia treating amount of a composition of the presentinvention.

Yet another aspect of this invention is directed to a method fortreating hypercholesterolemia in a mammal (including a human being) byadministering to a mammal in need of such treatment ahypercholesterolemia treating amount of a composition of the presentinvention.

Yet another aspect of this invention is directed to a method fortreating hypertriglyceridemia in a mammal (including a human being) byadministering to a mammal in need of such treatment ahypertriglyceridemia treating amount of a composition of the presentinvention.

Yet another aspect of this invention is directed to a method fortreating familial-hypercholesterolemia in a mammal (including a humanbeing) by administering to a mammal in need of such treatment afamilial-hypercholesterolemia treating amount of a composition of thepresent invention.

Yet another aspect of this invention is directed to a method fortreating cardiovascular disorders in a mammal (including a human being)by administering to a mammal in need of such treatment a cardiovasculardisorder treating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating angina in a mammal (including a human being) by administeringto a mammal in need of such treatment an angina treating amount of acomposition of the present invention.

Yet another aspect of this invention is directed to a method fortreating ischemia in a mammal (including a human being) by administeringto a mammal in need of such treatment an ischemic disease treatingamount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating cardiac ischemia in a mammal (including a human being) byadministering to a mammal in need of such treatment a cardiac ischemictreating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating stroke in a mammal (including a human being) by administeringto a mammal in need of such treatment a stroke treating amount of acomposition of the present invention.

Yet another aspect of this invention is directed to a method fortreating a myocardial infarction in a mammal (including a human being)by administering to a mammal in need of such treatment a myocardialinfarction treating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating reperfusion injury in a mammal (including a human being) byadministering to a mammal in need of such treatment a reperfusion injurytreating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating angioplastic restenosis in a mammal (including a human being)by administering to a mammal in need of such treatment an angioplasticrestenosis treating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating hypertension in a mammal (including a human being) byadministering to a mammal in need of such treatment a hypertensiontreating amount of a composition of the present invention.

Yet another aspect of this invention is directed to a method fortreating the vascular complications of diabetes in a mammal (including ahuman being) by administering to a mammal in need of such treatment avascular complications of diabetes treating amount of a composition ofthe present invention.

Yet another aspect of this invention is directed to a method fortreating obesity in a mammal (including a human being) by administeringto a mammal in need of such treatment an obesity treating amount of acomposition of the present invention.

Yet another aspect of this invention is directed to a method fortreating endotoxemia in a mammal (including a human being) byadministering to a mammal in need of such treatment an endotoxemiatreating amount of a composition of the present invention.

Other features and embodiments of the invention will become apparentfrom the following examples which are given for illustration of theinvention rather than for limiting its intended scope.

EXAMPLES Example 1

This example discloses preparation of an amorphous solid dispersion of[2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester (“Drug 1”), which has a solubility in water of lessthan 1 μg/mL and a Clog P value of 7.6. A dispersion of 10 wt % Drug 1and 90 wt % polymer was made by mixing Drug 1 in the solvent acetonetogether with a “medium fine” (AQUOT-MF) grade of the cellulosic esterpolymer HPMCAS (manufactured by Shin Etsu) to form a solution. Thesolution comprised 0.053 wt % Drug 1, 0.477 wt % HPMCAS, and 99.47 wt %acetone. The spray-dried dispersion (“SDD”) was prepared using a “mini”spray-dryer, which consisted of an atomizer in the top cap of avertically oriented stainless steel pipe. The atomizer was a two-fluidnozzle (Spraying Systems Co. 1650 fluid cap and 64 air cap), where theatomizing gas was nitrogen delivered to the nozzle at 100° C. and a flowrate of 15 gm/min, and the solution to be spray dried was delivered tothe nozzle at room temperature and a flow rate of 1.3 mL/min using asyringe pump. Filter paper with a supporting screen was clamped to thebottom end of the pipe to collect the solid spray-dried material andallow the nitrogen and evaporated solvent to escape. These SDDpreparation parameters are summarized in Table 1.

Control 1

Comparative composition Control 1 was simply 0.18 mg crystalline Drug 1.

Examples 2-3

Spray-dried dispersions were prepared using the procedure described inExample 1 except that the concentration-enhancing polymer was varied asnoted in Table 1.

Example 4

A spray-dried dispersion was prepared using the procedure described inExample 1 except that the ratio of Drug 1 to HPMCAS-MF was 1:1 (50 wt %Drug 1), as shown in Table 1.

TABLE 1 Drug 1 Concentration- Polymer Solvent Mass enhancing Mass MassSpray Example (mg) Polymer* (mg) Solvent (g) Apparatus 1 9 HPMCAS-MF 81acetone 17 Mini 2 3.8 HPMCP 33.7 acetone 6 Mini 3 3.5 PVP 31.5 Acetone/6 Mini MeOH 0.12 4 25 HPMCAS-MF 25 acetone 12 Mini *Polymerdesignations: HPMCAS = hydroxypropyl methyl cellulose acetate succinate;HPMCP = hydroxypropyl methyl cellulose phthalate; PVP =polyvinylpyrrolidone.

Example 5

The spray-dried dispersions of Examples 1 to 4 were evaluated in invitro dissolution tests using a microcentrifuge method. In this method,1 mg of the spray-dried dispersions was added to a 1.5-mLmicrocentrifuge tube. The tube was placed in a 37° C. sonicating bath,and 1 mL of a model-fasted duodenal solution (MFDS) (comprising sodiumtaurocholate/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(NaTC-POPC) in phosphate-buffered saline (PBS) at pH 6.5 and 290mOsm/kg) was added. The samples were quickly mixed using a combinationof vortex mixer and sonication for about 90 seconds. The theoreticalmaximum concentration (“TC_(max)”) of drug for Examples 1-3 if all thedrug dissolved was 100 μg/mL, while for Example 4 the TC_(max) was 500μg/mL. The samples were centrifuged at 13,000 G at 37° C. for 1 minute.The resulting supernatant solution was then sampled (100 μL) and dilutedwith 200 μL methanol and then analyzed by HPLC. The tubes were thenmixed on the vortex mixer and allowed to stand undisturbed at 37° C.until the next sample. Samples were collected at 3, 10, 30, 60, and 90minutes and for Examples 1 and 2 at 1200 minutes. Data for Examples 1 to4 are shown in Table 2.

For Control 1, an in vitro test was performed using the proceduredescribed above, except that 0.18 mg of crystalline Drug 1 was placed ina microcentrifuge tube and mixed with 1.8 mL of MFDS. The test resultsare included in Table 2.

TABLE 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL) 1 0 0 03 83 120 10 79 690 30 85 2,300 60 84 4,900 90 77 7,300 1200 26 64,400 20 0 0 3 81 122 10 75 670 30 75 2,200 60 64 4,200 90 74 6,300 1200 2158,700 3 0 0 0 3 35 53 10 33 290 30 30 900 60 28 1,800 90 28 2,600 4 0 00 3 62 94 10 63 530 30 54 1,700 60 52 3,300 90 40 4,700 Control 1 0 0 04 <0.1 <0.1 10 0.3 1 20 0.3 4 40 0.9 16 90 0.8 57

TABLE 3 Concentration- Concentration of enhancing Drug in In theTC_(max) C_(max, 90) AUC₉₀ Example Polymer* Dispersion (wt %) (μg/mL)(μg/mL) (min-μg/mL) 1 HPMCAS-MF 10 100 85 7300 2 HPMCP 10 100 81 6300 3PVP 10 100 35 2600 4 HPMCAS-MF 50 500 63 4700 Control 1 None — 100 0.957 *Polymer designations: HPMCAS = hydroxypropyl methyl celluloseacetate succinate; HPMCP = hydroxypropyl methyl cellulose phthalate, PVP= polyvinylpyrrolidone.

The results of the in vitro dissolution tests are summarized in Table 3,which shows the maximum concentration of Drug 1 in solution during the90-minute test (C_(max,90)), and the area under the aqueousconcentration versus time curve during the 90-minute test (AUC₉₀). Theresults show that the performance of the spray-dried dispersions ofExamples 1 to 4 was much better than that of the crystalline drug alone

(Control 1), with C_(max,90) values ranging from 39- to 94-fold that ofthe crystalline drug, Control 1, and AUC₉₀ values ranging from 45- to128-fold that of the crystalline drug, Control 1.

Examples 6-7

Examples 6-7 demonstrates the utility of the amorphous dispersions ofthe present invention with another CETP inhibitor,[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (“Drug 2”), which has a solubility in water of <1μg/ml, and a Clog P value of 7.5. To prepare Example 6, an amorphoussolid dispersion of 25 wt % Drug 2 and 75 wt % polymer was made bymixing Drug 2 in the solvent acetone together with a “medium fine”(AQUOT-MF) grade of the cellulosic ester polymer HPMCAS (manufac-turedby Shin Etsu) to form a solution. The solution comprised 2.5 wt % Drug2, 7.5 wt % HPMCAS, and 90 wt % acetone. This solution was thenspray-dried by directing an atomizing spray using a two-fluidexternal-mix spray nozzle at 2.7 bar (37 psig) at a feed rate of 150g/min into the stainless-steel chamber of a Niro PSD1 spray-dryer,maintained at a temperature of 155° C. at the inlet and 70° C. at theoutlet. The preparation parameters are summarized in Table 4. Theresulting amorphous solid spray-dried dispersion was collected via acyclone and then dried in a Gruenberg solvent tray-dryer by spreadingthe spray-dried particles onto polyethylene-lined trays to a depth ofnot more than 1 cm and then drying them at 40° C. for 24 hours.

Example 7 was prepared following the general procedure described inExample 6 except that the dispersion contained 10 wt % Drug 2 and thespray solution comprised 1.0 wt % Drug 2, 9.0 wt % HPMCAS-MF, and 90 wt% acetone. The preparation parameters are summarized in Table 4.

TABLE 4 Drug 2 Concentration- Polymer Solvent Mass enhancing Mass MassSpray Example (g) Polymer (g) Solvent (g) Apparatus 6 100 HPMCAS-MF 300acetone 3600 PSD-1 7 100 HPMCAS-MF 900 acetone 9000 PSD-1 Control 20.0018 none — — — —

Comparative composition Control 2 consisted of 1.8 mg of the crystallineform of Drug 2 alone.

Example 8

The spray-dried dispersions of Examples 6 and 7 were evaluated in an invitro dissolution test using a microcentrifuge method. In this test, thespray-dried dispersion was added to a microcentrifuge tube for a Drug 2dose of about 1000 μg/mL (7.2 mg for Example 6, 18 mg for Example 7).The tube was placed in a 37° C. sonicating bath, and 1.8 mL phosphatebuffered saline (PBS) at pH 6.5 and 290 mOsm/kg was added. The sampleswere quickly mixed using a vortex mixer for about 60 seconds. Thesamples were centrifuged at 13,000 G at 37° C. for 1 minute. Theresulting supernatant solution was then sampled and diluted 1:6 (byvolume) with methanol and then analyzed by high-performance liquidchromatography (HPLC). The contents of the tubes were mixed on thevortex mixer and allowed to stand undisturbed at 37° C. until the nextsample was taken. Samples were collected at 4, 10, 20, 40, 90, and 1200minutes. The concentrations of drug obtained in these samples are shownin Table 5.

For Control 2, an in vitro dissolution test was performed using theprocedures described above except that 1.8 mg of crystalline Drug 2 wasused. The concentrations of drug obtained in in vitro dissolution testsare shown in Table 5.

TABLE 5 Drug 2 Time Concentration AUC Example (mins) (μg/mL) (min-μg/mL)6 0 0 0 4 328 660 10 701 3,700 20 781 11,200 40 805 27,000 90 780 66,6001200 439 743,200 7 0 0 0 4 925 1,900 10 923 7,400 20 910 16,600 40 89034,600 90 858 78,300 1200 623 900,200 Control 2 0 0 0 4 <1 <2 10 <1 <820 <1 <18 40 <1 <38 90 <1 <88 1200 <1 <1,200The results of dissolution tests for Examples 6 and 7, and Control 2 aresummarized in Table 6, which shows the maximum concentration of Drug 2in solution during the first 90 minutes of the test (C_(max,90)), thearea under the aqueous concentration versus time curve after 90 minutes(AUC₉₀), and the concentration at 1200 minutes (C₁₂₀₀).

TABLE 6 Concentration- Drug 2 Conc. enhancing in the Receptor TC_(max)C_(max, 90) AUC₉₀ C₁₂₀₀ Example Polymer Dispersion (wt %) Solution(μg/mL) (μg/mL) (min-μg/mL) (μg/mL) 6 HPMCAS-MF 25 PBS 994 805 66,600439 7 HPMCAS-MF 10 PBS 988 925 78,300 623 Control 2 None NA PBS 1000 <1<88 <1 (crystalline drug)

The results summarized in Table 6 above show that the dissolutionresults for the compositions of Examples 6 and 7 were much better thanthat of the crystalline drug alone, providing C_(max,90) values thatwere greater than 805-fold and 925-fold that of the crystalline drug(Control 2), respectively, and AUC₉₀ values that were greater than756-fold and 889-fold that of the crystalline drug (Control 2),respectively. Accurate measurements of the solubility of crystallineDrug 2 yield a value of about 0.01 μg/ml. Thus, the actual C_(max,90)for Drug 2 in Control 2 is believed to be about 0.01 μg/ml. Using thisvalue, the compositions of Examples 6 and 7 provided C_(max,90) valuesthat were about 80,000-fold to 92,500-fold that of the crystalline drug,and AUC₉₀ values that were about 70,000- to 80,000-fold that of thecrystalline drug, respectively.

Examples 9-16

Spray-dried dispersions for Examples 9-16 were prepared using theprocedure described in Example 1 (using a “mini” spray-dryer apparatus)except that Drug 2 was used instead of Drug 1. Other variables aresummarized in Table 7.

Comparative composition Control 3 consisted of 0.72 mg of thecrystalline form of Drug 2 alone.

TABLE 7 Drug 2 Concentration- Polymer Solvent Mass enhancing Mass MassSpray Example (mg) Polymer* (mg) Solvent (g) Apparatus 9 70 HPMCAS-MF630 acetone 14 mini 10 70 CAT 630 acetone 14 mini 11 70 CAP 630 acetone14 mini 12 250 HPMCAS-MF 750 acetone 75 mini 13 25 CAP 75 acetone 5 mini14 3 HPMC 27 Acetone/ 10 mini Methanol (1:1) 15 3 HPMCP 27 Acetone 10mini 16 3 PVP 27 Acetone/ 10 mini Methanol (9:1) *Polymer designations:HPMCAS = hydroxypropyl methyl cellulose acetate succinate; CAT =cellulose acetate trimellitate, CAP = cellulose acetate phthalate, HPMC= hydroxypropyl methyl cellulose, HPMCP = hydroxypropyl methyl cellulosephthalate, PVP = polyvinylpyrrolidone.

Example 17

The dispersions of Examples 9-11 and 14 were evaluated in an in vitrodissolution test using receptor solutions of PBS using the proceduresoutlined in Example 8 except the TC_(max) was either 400 μg/ml or 100μg/ml as indicated in Table 9, depending on the amount of SDD added tothe receptor solution. The data are presented in Table 8.

The dispersions of Examples 9-16 were also evaluated in an in vitrodissolution test using receptor solutions of MFDS using the proceduresoutlined in Example 8. The data are also presented in Table 8.

For Control 3, an in vitro dissolution test was performed using theprocedure described above except that 0.72 mg of crystalline Drug 2 wasused. The results are shown in Table 8.

TABLE 8 Time Concentration AUC Example Receptor (min) (μg/ml)(min-μg/ml)  9 PBS 0 0 0 4 370 740 10 364 2,940 20 356 6,500 40 33613,500 90 318 29,800 1200 131 279,200  9 MFDS 0 0 0 4 391 780 10 3883,120 20 384 7,000 40 372 14,500 90 340 32,300 1200 110 282,300 10 PBS 00 0 4 375 750 10 366 2,970 20 360 6,600 40 321 13,400 90 300 28,900 120054 225,900 10 MFDS 0 0 0 4 395 789 10 386 3,130 20 368 6,900 40 34914,100 90 298 30,200 1200 92 246,400 11 PBS 0 0 0 4 383 764 10 381 3,05020 360 6,800 40 338 13,800 90 302 29,600 1200 56 228,600 11 MFDS 0 0 0 4409 818 10 380 3,190 20 374 7,000 40 357 14,300 90 326 31,300 1200 102268,700 12 MFDS 0 0 0 4 136 272 10 168 1,180 20 161 2,800 40 145 5,90090 122 12,600 1200 0 80,500 13 MFDS 0 0 0 4 285 571 10 277 2,260 20 2454,900 40 218 9,500 90 176 19,400 1200 57 149,000 14 PBS 0 0 0 3 70 10610 64 580 20 59 1,200 40 50 2,300 90 42 4,600 1200 18 37,900 14 MFDS 0 00 3 94 142 10 94 800 20 85 1,700 40 80 3,300 90 74 7,200 1200 28 63,70015 MFDS 0 0 0 3 98 147 10 83 780 20 67 1,500 40 56 2,800 90 46 5,3001200 25 44,500 16 MFDS 0 0 0 3 19 28 10 16 150 20 13 300 40 13 600 90 121,200 1200 15 16,100 Control 3 MFDS 0 0 0 4 <1 <4 10 <1 <10 20 <1 <20 40<1 <40 90 <1 <90The results summarized in Table 9 show that the dissolution results forthe compositions of Examples 9-16 were much better than that of thecrystalline drug alone, providing C_(max,90) values that were greaterthan 19- to 409-fold that of the crystalline drug (Control 3), whentested in MFDS, and AUC₉₀ values that were greater than 13- to 359-foldthat of the crystalline drug (Control 3), when tested in MFDS.

TABLE 9 Concentration- Conc. of enhancing Drug in the Receptor TC_(max)C_(max, 90) AUC₉₀ Example Polymer* Dispersion (wt %) Solution (μg/mL)(μg/mL) (min-μg/mL) 9 HPMCAS-MF 10 PBS 400 370 29,800 9 HPMCAS-MF 10MFDS 400 391 32,300 10 CAT 10 PBS 400 375 28,900 10 CAT 10 MFDS 400 39530,200 11 CAP 10 PBS 400 383 29,800 11 CAP 10 MFDS 400 409 31,300 12HPMCAS-MF 25 MFDS 400 168 12,600 13 CAP 25 MFDS 400 285 19,400 14 HPMC10 PBS 100 70 4,600 14 HPMC 10 MFDS 100 94 7,200 15 HPMCP 10 MFDS 100 985,300 16 PVP 10 MFDS 100 19 1,200 Control 3 None NA MFDS 400 <1 <90(crystalline drug) *Polymer designations: HPMCAS = hydroxypropyl methylcellulose acetate succinate; CAT = cellulose acetate trimellitate, CAP =cellulose acetate phthalate, HPMC = hydroxypropyl methyl cellulose,HPMCP = hydroxypropyl methyl cellulose phthalate, PVP =polyvinylpyrrolidone.

Examples 18-20

These Examples demonstrate that the technology of this invention, whenorally dosed to beagle dogs, gives a high systemic compound exposure(C_(max) and AUC). Spray-dried dispersions were made using theprocedures outlined in Examples 6, 7 and 11, and were used as an oralpowder for constitution (OPC) by suspending 360 mg of the composition ofExample 6 in about 15 mL of a solution of 3 wt % polyethylglycol (PEG)with a molecular weight of 3,350 daltons, 0.5 wt % methylcellulose, and0.15 wt % Polysorbate 80 in sterile water (Example 18), suspending 900mg of the composition of Example 7 in about 15 mL of a solution of 3 wt% PEG with a molecular weight of 3,350 daltons, 0.5 wt %methylcellulose, and 0.15 wt % Polysorbate 80 in sterile water (Example19), and by suspending 900 mg of the composition of Example 11 in about15 mL of a solution of 3 wt % PEG with a molecular weight of 3,350daltons, 0.5 wt % methylcellulose, and 0.15 wt % Polysorbate 80 insterile water (Example 20). A control OPC containing 90 mg ofcrystalline drug was also prepared by suspending 90 mg of crystallinedrug in about 15 ml of a solution of 3 wt % PEG with a molecular weightof 3,350 daltons, 0.5 wt % methyl cellulose, and 0.15 wt % polysorbate80 in sterile water (Control 4). Dogs that had fasted overnight weredosed with the OPC. Blood was collected from the jugular vein of thedogs before dosing and at various time points after dosing. To 100 μL ofeach plasma sample, 5 mL of methyl-tert-butyl ether (MTBE) and 1 mL of500 mM sodium carbonate buffer (pH 9) were added; the sample wasvortexed for 1 minute and then centrifuged for 5 minutes. The aqueousportion of the sample was frozen in a dry-ice/acetone bath, and the MTBElayer was decanted and evaporated in a vortex evaporator. Dried sampleswere reconstituted in 100 μL of mobile phase (33% acetonitrile and 67%of 0.1% formic acid in water). Analysis was carried out by HPLC.

The results of these tests are shown in Table 10, where C_(max,24) isthe maximum concentration in the blood plasma during the first 24 hours,T_(max) is the time to achieve the maximum concentration in the bloodplasma and AUC₀₋₂₄ is the concentration in the blood plasma area underthe curve in the first 24 hours. The results show that the C_(max,24)and AUC₀₋₂₄ in the blood were much higher for the compositions of thepresent invention than the controls, with C_(max,24) values that are21.5- to 40-fold that of the crystalline drug (Control 4), and AUC₀₋₂₄values that are 21.7- to 55.6-fold that of the crystalline drug (Control4).

TABLE 10 Dose C_(max, 24) T_(max) AUC₀₋₂₄ Example Formulation (mg)(μg/mL) (hr) (μg-hr/mL) 18 25% Drug 2: HPMCAS OPC 90 1.60 ± 0.60 1.10 ±0.50 7.88 ± 2.95 19 10% Drug 2: HPMCAS OPC 90 0.86 ± 1.75 2.17 ± 1.943.47 ± 1.71 20 10% Drug 2: CAP OPC 90 1.51 ± 0.50 1.58 ± 1.28 8.89 ±1.75 Control 4 Crystalline Drug 2 90 0.04 ± 0.01 1.33 ± 0.52 0.16 ± 0.14suspension

Examples 21-28

Example 21 demonstrates the utility of the amorphous dispersions of thepresent invention with another CETP inhibitor,[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester (“Drug 3”), which has a solubility in water of lessthan 0.1 μg/ml, and a Clog P value of 8.0. To prepare Example 21, anamorphous solid dispersion of a CETP inhibitor comprising 10 wt % Drug 3and 90 wt % polymer was made by mixing Drug 3 in the solvent acetonetogether with HPMCAS-MF to form a solution. The solution comprised 0.1wt % Drug 3, 0.9 wt % HPMCAS, and 99 wt % acetone. This solution waspumped into a “mini” spray-dryer apparatus via a syringe pump at a rateof 1.3 mL/min. The polymer solution was atomized through a spray nozzleusing a heated stream of nitrogen. The resulting solid spray-drieddispersion was collected on a filter paper at a yield of about 50%. Thepreparation parameters are summarized in Table 11.

Spray-dried dispersions were prepared using the procedure described toprepare Example 21 except that the aqueous-soluble polymer and sometimesthe solvent was varied as noted in Table 11.

Comparative composition Control 5 consisted of 0.72 mg of thecrystalline form of Drug 3 alone.

TABLE 11 Drug 3 Concentration- Polymer Solvent Mass enhancing Mass MassSpray Example (mg) Polymer* (mg) Solvent (g) Apparatus 21 20 HPMCAS-MF180 Acetone 20 mini 22 10 HPMCP 90 Acetone 10 mini 23 10 CAP 90 Acetone10 mini 24 10 CAT 90 Acetone 10 mini 25 10 PVP 90 Acetone 9 miniMethanol 1 26 10 HPMC 90 Methanol 10 mini 27 10 HPMCAS-LF 90 Acetone 10mini 28 10 HPMCAS-HF 90 Acetone 10 mini *Polymer designations: HPMCAS =hydroxypropyl methyl cellulose acetate succinate; HPMCP = hydroxypropylmethyl cellulose phthalate, CAP = cellulose acetate phthalate, CAT =cellulose acetate trimellitate, PVP = polyvinylpyrrolidone, HPMC =hydroxypropyl methyl cellulose.

Example 29

The spray-dried dispersions of Examples 21-28 were evaluated in an invitro dissolution test using a microcentrifuge method. In this method,7.2 mg of each spray-dried dispersion was added to a 2-mLmicrocentrifuge tube. The tube was placed in a 37° C. sonicating bath,and 1.8 mL of a phosphate-buffered saline (PBS) solution at pH 6.5 and290 mOsm/kg was added, resulting in a TC_(max) of 400 μg/mL. The sampleswere quickly mixed using a combination of vortex mixer and sonicationfor about 90 seconds. The samples were centrifuged at 13,000 G at 37° C.for 1 minute. The resulting supernatant solution was then sampled anddiluted 1:6 (by volume) with methanol and then analyzed by HPLC. Thetubes were then mixed on the vortex mixer and allowed to standundisturbed at 37° C. until the next sample. Samples were collected at4, 10, 20, 40, 90 and 1200 minutes. Data are included in Table 12.

For Control 5, an in vitro dissolution test was performed using theprocedure described above, except that 0.72 mg of non-crystalline Drug 3was placed in a microcentrifuge tube and mixed with 1.8 mL of PBS. Thetest results are included in Table 12.

TABLE 12 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL) 21 0 00 4 347 694 10 361 2,800 20 370 6,500 60 396 14,000 90 364 33,100 1200291 396,500 22 0 0 0 4 373 685 10 296 2,600 20 264 5,400 40 231 10,40090 174 20,500 1200 33 135,000 23 0 0 0 4 384 769 10 368 3,000 20 3766,700 40 356 14,100 90 371 32,200 1200 237 369,700 24 0 0 0 4 390 780 10390 3,100 20 386 7,000 40 387 14,700 90 379 33,900 1200 231 372,400 25 00 0 4 196 392 10 158 1,500 20 145 3,000 40 134 5,800 90 127 12,300 120084 129,400 26 0 0 0 4 346 693 10 349 2,800 20 343 6,200 40 323 12,900 90296 28,400 1200 209 308,700 27 0 0 0 4 373 746 10 348 2,900 20 335 6,30040 315 12,800 90 292 28,000 1200 195 298,300 28 0 0 0 4 72 144 10 172876 20 316 3,300 40 370 10,200 90 405 29,600 1200 355 451,400 Control 50 0 0 4 <0.1 <0.4 10 <0.1 <1.0 20 <0.1 <2.0 40 <0.1 <4.0 90 <0.1 <9.0

The results, summarized in Table 13, show that the dissolution resultsfor the compositions of Examples 21 through 28 were much better thanthat of the crystalline drug alone, providing C_(max,90) values thatwere greater than 1,900- to 4,050-fold that of the crystalline drug(Control 5), and AUC₉₀ values that were greater than 1,370- to3.770-fold that of the crystalline drug (Control 5).

TABLE 13 Concentration- Concentration enhancing of Drug 3 in C_(max, 90)AUC₉₀ Example Polymer* Polymer (wt %) (μg/mL) (min-μg/mL) 21 HPMCAS-MF10 396 33,100 22 HPMCP 10 343 20,500 23 CAP 10 384 32,200 24 CAT 10 39033,900 25 PVP 10 196 12,300 26 HPMC 10 349 28,400 27 HPMCAS-LF 10 37328,000 28 HPMCAS-HF 10 405 29,600 Control 5 None — <0.1 <9.0 *Polymerdesignations: HPMCAS = hydroxypropyl methyl cellulose acetate succinate;HPMCP = hydroxypropyl methyl cellulose phthalate, CAP = celluloseacetate phthalate, CAT = cellulose acetate trimellitate, PVP =polyvinylpyrrolidone, HPMC = hydroxypropyl methyl cellulose.

Examples 30-41

Examples 30 through 41 demonstrate the utility of the amorphousdispersions of the present invention with a variety of CETP inhibitors.The following drugs were all incorporated into solid amorphousdispersions:[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (“Drug 4”);[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (“Drug 5”);[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid ethyl ester (“Drug 6”);[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester (“Drug 7”);[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester (“Drug 8”);[3S,5S]2-cyclopentyl-4-(4-fluoro-phenyl)-3-[fluoro-(4-trifluoromethyl-phenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-5-ol(“Drug 9”). All of these compounds have a solubility in water of lessthan 1 μg/ml, with Clog P values ranging from 5.5 to 8.3. To prepareExamples 30-41, dispersions comprising 10 wt % drug and 90 wt % polymerwere made by mixing each drug in the solvent acetone together withpolymer to form a solution. Dispersions with HPMCAS-MF and CAP wereprepared for each drug. The solutions comprised 0.05 wt % drug, 0.45 wt% polymer, and 99.5 wt % acetone. Each solution was pumped into a “mini”spray-dryer apparatus via a syringe pump at a rate of 1.3 mL/min. Thepolymer solution was atomized through a spray nozzle using a heatedstream of nitrogen. The resulting solid spray-dried dispersion wascollected on a filter paper at a yield of about 65%. The preparationparameters are summarized in Table 14.

Controls 6-11

The comparative compositions of Controls 6-11 consisted of 1.5 mg of thecrystalline form of each of Drugs 4-9 alone.

TABLE 14 Drug Concentration- Polymer Solvent Drug Mass enhancing MassMass Spray Example No. (mg) Polymer* (mg) Solvent (g) Apparatus 30 4 5HPMCAS-MF 45 acetone 10 mini 31 4 5 CAP 45 acetone 10 mini 32 5 5HPMCAS-MF 45 acetone 10 mini 23 5 5 CAP 45 acetone 10 mini 34 6 5HPMCAS-MF 45 acetone 10 mini 35 6 5 CAP 45 acetone 10 mini 36 7 5HPMCAS-MF 45 acetone 10 mini 37 7 5 CAP 45 acetone 10 mini 38 8 5HPMCAS-MF 45 acetone 10 mini 39 8 5 CAP 45 acetone 10 mini 40 9 5HPMCAS-MF 45 acetone 10 mini 41 9 5 CAP 45 acetone 10 mini *Polymerdesignations: HPMCAS = hydroxypropyl methyl cellulose acetate succinate,CAP = cellulose acetate phthalate.

Example 42

The spray-dried dispersions of Examples 30-41 were evaluated in an invitro dissolution test using a microcentrifuge method. In this method,15 mg of each SDD was added to a 2-mL microcentrifuge tube. The tube wasplaced in a 37° C. sonicating bath, and 1.5 mL of a phosphate-bufferedsaline (PBS) solution at pH 6.5 and 290 mOsm/kg) was added, resulting ina TC_(max) of 1000 μg/mL. The samples were quickly mixed using acombination of vortex mixer and sonication for about 90 seconds. Thesamples were centrifuged at 13,000 G at 37° C. for 1 minute. Theresulting supernatant solution was then sampled and diluted 1:6 (byvolume) with methanol and then analyzed by HPLC. The tubes were thenmixed on the vortex mixer and allowed to stand undisturbed at 37° C.until the next sample. Samples were collected at 4, 10, 20, 40, and 90minutes. Data are included in Table 15.

For Controls 6-11, an in vitro dissolution test was performed using theprocedure described above, except that 1.5 mg of non-crystalline drugwas placed in a microcentrifuge tube and mixed with 1.5 mL of PBS. Thetest results are included in Table 15.

TABLE 15 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL) 30 0 00 4 999 2,000 10 836 7,500 20 729 15,300 60 571 28,300 90 471 54,400 310 0 0 4 591 1,200 10 599 4,800 20 557 10,500 40 500 21,100 90 427 44,30032 0 0 0 4 1091 2,200 10 1079 8,700 20 1061 19,400 40 1033 40,300 90 98590,800 33 0 0 0 4 836 1,700 10 965 7,100 20 971 16,800 40 973 36,200 90943 84,100 34 0 0 0 4 852 1,700 10 890 6,900 20 896 15,900 40 852 33,30090 781 74,200 35 0 0 0 4 536 1,100 10 623 4,600 20 650 10,900 40 71324,500 90 610 57,600 36 4 0 0 10 947 1,900 20 912 7,500 40 876 16,400 90832 33,500 1200 783 73,900 37 0 0 0 4 262 500 10 559 3,000 20 638 9,00040 643 21,800 90 590 52,600 38 0 0 0 4 974 1,900 10 965 7,800 20 93317,300 40 935 35,900 90 969 83,500 39 0 0 0 4 705 1,400 10 811 6,000 20860 14,300 40 952 32,400 90 1003 81,300 40 0 0 0 4 224 400 10 503 2,60020 633 8,300 40 699 21,600 90 785 58,700 41 0 0 0 4 196 400 10 342 2,00020 527 6,400 40 520 16,800 90 596 44,700 Control 6 0 0 0 4 <1 <4 10 <1<10 20 <1 <20 40 <1 <40 90 <1 <90 Control 7 0 0 0 4 <1 <4 10 <1 <10 20<1 <20 40 <1 <40 90 <1 <90 Control 8 4 <1 <4 10 <1 <10 20 <1 <20 40 <1<40 90 <1 <90 Control 9 0 0 0 4 <1 <4 10 <1 <10 20 <1 <20 40 <1 <40 90 ——  Control 10 0 0 0 4 <1 <4 10 <1 <10 20 <1 <20 40 <1 <40 90 <1 <90 Control 11 0 0 0 4 <1 <4 10 <1 <10 20 <1 <20 40 <1 <40 90 <1 <90The results, summarized in Table 16, show that the dissolution resultsfor the compositions of Examples 30 through 41 were much better thanthat of each crystalline drug alone, providing C_(max,90) values thatwere greater than 596- to 1091-fold that of each respective crystallinedrug (Controls 6-11), and AUC₉₀ values that were greater than 490- to1,000-fold that of each respective crystalline drug.

TABLE 16 Conc. of Concentration- Drug in Drug enhancing PolymerC_(max, 90) AUC₉₀ Example No. Polymer* (wt %) (μg/mL) (min-μg/mL) 30 4HPMCAS-MF 10 999 54,400 31 4 CAP 10 599 44,300 32 5 HPMCAS-MF 10 109190,800 33 5 CAP 10 973 84,100 34 6 HPMCAS-MF 10 896 74,200 35 6 CAP 10713 57,600 36 7 HPMCAS-MF 10 947 73,900 37 7 CAP 10 643 52,600 38 8HPMCAS-MF 10 974 83,500 39 8 CAP 10 1003 81,300 40 9 HPMCAS-MF 10 78558,700 41 9 CAP 10 596 44,700 Control 6 4 None — <1 <90 Control 7 5 None— <1 <90 Control 8 6 None — <1 <90 Control 9 7 None — <1 <90  Control 108 None — <1 <90  Control 11 9 None — <1 <90 *Polymer designations:HPMCAS = hydroxypropyl methyl cellulose acetate succinate, CAP =cellulose acetate phthalate.

Examples 43-46

Examples 43 through 46 demonstrate the utility of the amorphousdispersions of the present invention with two additional CETPinhibitors. The following drugs were incorporated into solid amorphousdispersions:(4′S)-5′-(4-fluorophenyl)-6′-[(S)-fluoro[4-(trifluoromethyl)phenyl]methyl]-3′,4′-dihydro-7′-(1-methylethyl)-spiro[cyclobutane-1,2′(1′H)-naphthalen]-4′-ol(“Drug 10”), and(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol(“Drug 11”). These compounds have a solubility in water of less than 1μg/mL, with Clog P values of 8.9 and 9.8, respectively. To prepareExamples 43 through 46, dispersions comprising 10 wt % drug and 90 wt %polymer were made by first mixing each drug in the solvent acetonetogether with polymer to form a solution. Dispersions with HPMCAS-MF andCAP were prepared for each drug. The solutions comprised 0.05 wt % drug,0.45 wt % polymer, and 99.5 wt % acetone. Each solution was pumped intoa “mini” spray-dryer apparatus via a syringe pump at a rate of 1.3mL/min. The polymer solution was atomized through a spray nozzle using aheated stream of nitrogen. The resulting solid spray-dried dispersionwas collected on a filter paper at a yield of about 40%. The preparationparameters are summarized in Table 17.

TABLE 17 Drug Concentration- Polymer Solvent Drug Mass enhancing MassMass Spray Example No. (mg) Polymer* (mg) Solvent (g) Apparatus 43 10 5HPMCAS-MF 45 Acetone 10 mini 44 10 5 CAP 45 Acetone 10 mini 45 11 5HPMCAS-MF 45 Acetone 10 mini 46 11 5 CAP 45 Acetone 10 mini *Polymerdesignations: HPMCAS = hydroxypropyl methyl cellulose acetate succinate,CAP = cellulose acetate phthalate.

Controls 12-13

The comparative compositions of Controls 12 and 13 consisted of 1.0 mgof the undispersed amorphous form of each of Drugs 10 and 11 alone.

Example 47

The spray-dried dispersions of Examples 43 to 46 were evaluated in an invitro dissolution test using a microcentrifuge method. In this method,10 mg of each SDD was added to a 2-mL microcentrifuge tube. The tube wasplaced in a 37° C. sonicating bath, and 1.0 mL of a phosphate-bufferedsaline (PBS) solution at pH 6.5 and 290 mOsm/kg was added, resulting ina TC_(max) of 1000 μg/mL. The samples were quickly mixed using acombination of vortex mixer and sonication for about 90 seconds. Thesamples were centrifuged at 13,000 G at 37° C. for 1 minute. Theresulting supernatant solution was then sampled and diluted 1:6 (byvolume) with methanol and then analyzed by HPLC. The tubes were thenmixed on the vortex mixer and allowed to stand undisturbed at 37° C.until the next sample. Samples were collected at 4, 10, 20, 40, 90, and1200 minutes. Data are included in Table 19.

For Controls 12 and 13, an in vitro dissolution test was performed usingthe procedure described above, except that 1.0 mg of undispersedamorphous drug was placed in a microcentrifuge tube and mixed with 1.0mL of PBS. The test results are included in Table 18.

TABLE 18 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL) 43 0 00 (Drug 10) 4 540 1,100 10 680 4,700 30 780 12,000 60 880 28,600 90 88072,700 1200 900 1,064,000 44 0 0 0 (Drug 10) 4 470 900 10 540 4,000 20650 9,900 40 730 23,700 90 810 62,200 1200 840 979,900 45 0 0 0 (Drug11) 4 700 1,400 10 890 6,200 20 980 15,500 40 970 35,000 90 1040 85,1001200 1140 1,296,100 46 0 0 0 (Drug 11) 4 920 1,800 10 1110 8,000 20 112019,200 40 1030 40,700 90 1030 92,300 1200 920 1,177,400 Control 12 0 0 0(Drug 10) 4 0 0 10 1 0 20 3 0 40 6 100 90 1 300 1200 0 1,100 Control 130 0 0 (Drug 11) 4 1 0 10 1 0 20 1 0 40 1 0 90 1 100 1200 0 600

The results, summarized in Table 19, show that the dissolution resultsfor the compositions of Examples 43 through 46 were much better thanthat of each drug alone, providing C_(max,90) values that were 135- to1120-fold that of each respective undispersed amorphous drug (Controls12 and 13), and AUC₉₀ values that were 207- to 1,150-fold that of eachrespective drug alone.

TABLE 19 Concentration- Concentration Drug enhancing of Drug inC_(max, 90) AUC₉₀ Example No. Polymer* Polymer (wt %) (μg/mL)(min-μg/mL) 43 10 HPMCAS-MF 10 880 72,700 44 10 CAP 10 810 62,200 45 11HPMCAS-MF 10 1040 85,100 46 11 CAP 10 1120 92,300 Control 12 10 None — 6300 Control 13 11 None — 1 80 *Polymer designations: HPMCAS =hydroxypropyl methyl cellulose acetate succinate, CAP = celluloseacetate phthalate.

Examples 48-53

The suitability of forming solid amorphous dispersions comprising Drug 2and HPMCAS-MF via a melt-congeal or melt-extrusion process was evaluatedusing a differential scanning calorimeter (DSC). In this technique, adry blend of the desired mount of Drug 2 and HPMCAS-MF was formed byadding the ingredients to a container and mixing with a spatula. About10 mg of this dry blend was then placed in a DSC sample pan andhermetically sealed. The sample pan was then placed into a Perkin-ElmerPyris-1 DSC and the sample heated to the desired hold temperature at arate of about 50° C./min and held at this temperature for 1 hour. Thesample was then cooled to ambient temperature at a rate of about 50°C./min. The glass-transition temperature of the heated sample was thendetermined by scanning the sample on the DSC at a constant temperaturerate of 10° C./min. Table 20 gives the compositions evaluated and thehold temperatures evaluated as well as the results of the DSC scansafter holding at the final temperature for 1 hour.

TABLE 20 Results of DSC Evaluation Drug 2 Hold After Holding at theConcentration Temperature Hold Temperature for 1 Hour Example (wt %) (°C.) (Tg in ° C.) 48 10 100 Two T_(g)s seen (~35°, ~120°) 49 10 125Single T_(g) (~100°) 50 10 150 Single T_(g) (~100°) 51 25 100 Two T_(g)sSeen (~35°, ~120°) 52 25 125 Two T_(g)s seen (small peak at ~35°, largeat 100° C.) 53 25 150 Single T_(g) (~90° C.)

These data show that at a Drug 2 concentration of 10 wt %, a solidamorphous dispersion could be formed by holding the materials at 125° C.for 1 hour. The resulting material had a single T_(g) at about 100° C.—between the T_(g) assigned to amorphous Drug 2 (˜35° C.) and the T_(g)of HPMCAS-MF (−120° C.). The data indicate that heating a mixture of 10wt % Drug 2 and HPMCAS-MF to 125° C. or higher and holding it at thattemperature for 1 hour will result in a homogeneous, solid amorphousdispersion.

The data also show that at a Drug 2 concentration of 25 wt %, holdingthe material at 125° C. resulted in a material with two T_(g)s. Thesmall peak at about 35° C. suggests that the sample contained a smallamount of amorphous drug and was therefore not a homogeneous dispersion,but likely a mixture of amorphous Drug 2 and a Drug 2:HPMCAS-MFamorphous dispersion. However, heating to 150° C. for 1 hour (Example53) did result in a homogeneous, amorphous dispersion, as evidenced bythe single T_(g). Note that the T_(g) for the homogeneous, amorphousdispersion containing 25 wt % Drug 2 (Example 53) was somewhat lowerthan the T_(g) of the homogeneous, amorphous dispersion containing 10 wt% Drug 2 (Example 50). This was as expected since the dispersion ofExample 53 contained a larger fraction of Drug 2, which has a T_(g) thatis lower than that of HPMCAS.

Examples 54-55

A solid amorphous dispersion of Drug 2 and HPMCAS-MF was prepared bymelt-extrusion using the following procedure. For Example 54, a blend of25 wt % Drug 2 and 75 wt % HPMCAS-MF was formed by mixing 3.75 gm ofDrug 2 and 11.25 gm of HPMCAS-MF in a Turbula mixer for 10 minutes. ForExample 55, a blend of 25 wt % Drug 2 and 75 wt % HPMCAS-MF was formedby mixing 12.5 gm of Drug 2 and 37.5 gm of HPMCAS-MF in a Turbula mixerfor 10 minutes. These pre-blended feeds were fed to a DACAMicro-Compounder (Goleta, Calif.) equipped with conical co-rotatingscrews. For Example 54, the extruder was set at a temperature of 150° C.and the screw speed was set at 40 RPM. For Example 55, the extruder wasset at a temperature of 140° C. and the screw speed was set at 120 RPM.In both cases, the extrudate exited the extruder in the form ofcylindrical rods with a diameter of about 3 mm. The molten extrudate wastransparent with a slight yellow color. The extrudate was cooled withambient air, with the outside surface of the rod becoming solid within afew seconds after exiting the extruder. After solidification, the solidamorphous dispersion was transparent with a slight yellow color and wasvery brittle.

The extrudate was collected and milled in a SPEX 6800 cryogenic freezermill (SPEX CertiPrep, Metuchen, N.J.) set at 10 impacts/sec, 1 cycle,with a 2-minute pre-cool, followed by 5 minutes of milling.

Example 56

The solid amorphous dispersions of Example 54 to 55 were evaluated in anin vitro dissolution test using the procedures described in Example 8except that a MFD solution was used as the receptor solution. Theresults of these tests are presented in Table 21.

TABLE 21 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)54 0 0 0 4 53 110 10 189 830 20 293 3,200 40 443 10,600 90 516 34,6001200 265 467,700 55 0 0 0 4 175 350 10 267 1,700 20 363 4,800 40 45213,000 90 452 35,600 1200 117 351,400

The results are also summarized in Table 22, which also includes thedata for Control 3 which was tested under the same conditions. Thesedata show that the dispersions made by extrusion provided C_(max,90)values that were greater than 452- to 516-fold that of the crystallinecontrol (Control 3) and AUC₉₀ values that were greater than 384- to396-fold that of the crystalline control.

TABLE 22 Concentration- Concentration enhancing of Drug in C_(max, 90)AUC₉₀ Example Polymer* Polymer (wt %) (μg/mL) (min-μg/mL) 54 HPMCAS-MF25 516 34,600 55 HPMCAS-MF 25 452 35,600 Control 3 None — <1 <90*Polymer designation: HPMCAS = hydroxypropyl methyl cellulose acetatesuccinate

Examples 57-64

Solid amorphous dispersions of Drug 2 and the poloxamers Pluronic F-127and Pluronic F-108 (both supplied by BASF) were prepared by amelt-congeal process using the following procedure. For each example,the amount of Drug 2 and poloxamer given in Table 23 were accuratelyweighed and placed into a container. The container was then placed in ahot oil bath maintained at 105° C. After about 15 minutes, the mixturehad melted, and was stirred using a magnetic stirrer for about 15minutes. The molten mixture was transparent, with no apparent color.Next, the container containing the molten mixture was removed from thehot oil bath and placed into liquid nitrogen, resulting insolidification of the molten mixture within a few seconds. The containerwas removed from the liquid nitrogen after about 60 seconds and allowedto warm to ambient temperature. The resulting opaque solid amorphousdispersion was then removed from the container using a spatula andbroken into small pieces about 1 mm thick. The pieces were then placedinto a mortar with some liquid nitrogen and ground into a white powderusing a pestle.

TABLE 23 Concentration Drug Aqueous- Polymer of Drug in Mass SolubleMass Example Polymer (wt %) (gm) Polymer (gm) 57 10 0.1003 PluronicF-127 0.8999 58 25 0.2499 Pluronic F-127 0.7502 59 40 0.4020 PluronicF-127 0.6002 60 50 0.5024 Pluronic F-127 0.4992 61 60 1.2005 PluronicF-127 0.8024 62 70 0.3517 Pluronic F-127 0.1502 63 80 0.8007 PluronicF-127 0.2004 64 25 0.2494 Pluronic F-108 0.7494

Example 65

The solid amorphous dispersions of Example 57 to 64 were evaluated in anin vitro dissolution test using the procedures described in Example 8.The amount of each dispersion added to the microcentrifuge tube wasadjusted such that the concentration of Drug 2 in solution if all of thedrug had dissolved was 1000 μg/ml. The results of these tests arepresented in Table 24.

TABLE 24 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)57 0 0 0 4 930 1,900 10 899 7,300 20 856 16,100 40 806 32,800 90 71570,800 1200 385 681,700 58 0 0 0 4 699 1,400 10 653 5,500 20 594 11,70040 551 23,100 90 438 47,900 1200 184 392,800 59 0 0 0 4 264 500 10 2532,100 20 224 4,500 40 229 9,000 90 180 19,200 1200 90 169,100 60 0 0 0 4305 600 10 272 2,300 20 250 4,900 40 233 9,800 90 193 20,400 1200 76169,300 61 0 0 0 4 119 200 10 122 1,000 20 108 2,100 40 114 4,300 90 979,600 1200 51 90,000 62 0 0 0 4 43 90 10 48 400 20 58 900 40 56 2,000 9056 4,900 1200 34 54,900 63 0 0 0 4 14 30 10 17 100 20 19 300 40 18 70090 17 1,500 1200 10 16,800 64 0 0 0 4 542 1,100 10 496 4,200 20 4599,000 40 397 17,500 90 318 35,400 1200 66 248,800

The results are summarized in Table 25, which also includes the data forControl 2, which was tested under the same conditions. The results showthat the dissolution results for the compositions of Examples 57 through64 were much better than that of the crystalline drug alone (Control 2),providing C_(max,90) values that were greater than 19-fold to 930-foldthat of the crystalline drug alone, and AUC₉₀ values that were greaterthan 17-fold to 804-fold that of the crystalline drug alone.

TABLE 25 Concentration- Concentration enhancing of Drug in C_(max, 90)AUC₉₀ Example Polymer Polymer (wt %) (μg/mL) (min-g/mL) 57 PluronicF-127 10 930 70,800 58 Pluronic F-127 25 699 47,900 59 Pluronic F-127 40264 19,200 60 Pluronic F-127 50 305 20,400 61 Pluronic F-127 60 1229,600 62 Pluronic F-127 70 58 4,900 63 Pluronic F-127 80 19 1,500 64Pluronic F-108 25 542 35,400 Control 2 None — <1 <88

Examples 66-68

Spray-dried solid amorphous dispersions of Drug 2 and the poloxamersPluronic F-127 and Pluronic F-108 were prepared following the proceduresoutlined in Examples 43 through 46. Table 26 summarizes the preparationparameters.

TABLE 26 Drug Concentration- Polymer Solvent Drug Mass enhancing MassMass Spray Ex. No. (g) Polymer (g) Solvent (g) Apparatus 66 2 0.2502Pluronic 0.7501 Acetone 116 mini F-127 67 2 0.2154 Pluronic 0.2163Acetone 54.5 mini F-127 68 2 0.0728 Pluronic 0.2199 Acetone 44.15 miniF-108

Example 69

The spray-dried dispersions of Examples 66 to 68 were evaluated in an invitro dissolution test using the procedures described in Example 8. Theamount of each dispersion added to the microcentrifuge tube was adjustedsuch that the concentration of Drug 2 in solution if all of the drug haddissolved was 1000 μg/ml. The results of these tests are presented inTable 27.

TABLE 27 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)66 0 0 0 4 508 1,000 10 449 3,900 30 420 8,200 60 371 16,100 90 27232,200 1200 125 253,000 67 0 0 0 4 126 300 10 150 1,100 20 164 2,600 40151 5,800 90 148 13,300 1200 62 129,600 68 0 0 0 4 267 500 10 239 2,10020 221 4,400 40 196 8,500 90 143 17,000 1200 36 116,200

The results are summarized in Table 28, which also includes the data forControl 2, which was tested under the same conditions. The results showthat the dissolution results for the compositions of Examples 66 through68 were much better than that of the crystalline drug alone (Control 2),providing C_(max,90) values that were greater than 164-fold to 508-foldthat of the crystalline drug alone, and AUC₉₀ values that were greaterthan 151-fold to 365-fold that of the crystalline drug alone.

TABLE 28 Concentration- Concentration enhancing of Drug in theC_(max, 90) AUC₉₀ Example Polymer Dispersion (wt %) (μg/mL) (min-μg/mL)66 Pluronic F-127 25 508 32,200 67 Pluronic F-127 50 164 13,300 68Pluronic F-108 25 267 17,000 Control 2 None — <1 <88

Examples 70-72

Spray-dried solid amorphous dispersions of Drug 7 and CMEC (carboxymethyl ethyl cellulose, Freund Industrial Co. Ltd., Tokyo, Japan) wereprepared following the procedures outlined in Examples 43 through 46.Table 29 summarizes the preparation parameters. Example 70 comprised 25wt % Drug 7, Example 71 comprised 35 wt % Drug 7, and Example 72comprised 50 wt % Drug 7.

TABLE 29 Drug Concentration- Polymer Solvent Drug Mass enhancing MassMass Spray Ex. No. (g) Polymer* (g) Solvent (g) Apparatus 70 7 0.0626CMEC 0.1875 1:1 Ethanol: 12.8 mini Ethylacetate 71 7 0.2100 CMEC 0.39011:1 Ethanol: 30.0 mini Ethylacetate 72 7 0.1250 CMEC 0.1251 1:1 Ethanol:12.8 mini Ethylacetate *Polymer designation: CMEC = carboxymethyl ethylcellulose

Example 73

The spray-dried dispersions of Examples 70 to 72 were evaluated in an invitro dissolution test using the procedures described in Example 8. Theamount of each dispersion added to the microcentrifuge tube was adjustedsuch that the concentration of Drug 7 in solution if all of the drug haddissolved was 1000 μg/ml. The results of these tests are presented inTable 30.

TABLE 30 Drug 7 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)70 0 0 0 4 892 1,800 10 897 7,200 30 888 16,100 60 812 33,076 90 62268,900 1200 90 464,100 71 0 0 0 4 521 1,000 10 538 4,200 20 482 9,300 40382 18,000 90 323 35,600 1200 111 276,500 72 0 0 0 4 82 200 10 153 90020 167 2,500 40 163 5,800 90 151 13,600 1200 83 143,500

The results are summarized in Table 31, which also includes the data forControl 9 (Drug 7 alone), which was tested under the same conditions.The results show that the dissolution results for the compositions ofExamples 70 through 72 were much better than that of the crystallinedrug alone (Control 9), providing C_(max,90) values that were greaterthan 167-fold to 897-fold that of the crystalline drug alone, and AUC₉₀values that were greater than 155-fold to 783-fold that of thecrystalline drug alone.

TABLE 31 Concentration Concentration- of Drug in the enhancingDispersion C_(max, 90) AUC₉₀ Example Polymer (wt %) (μg/mL) (min-μg/mL)70 CMEC 25 897 68,900 71 CMEC 35 538 35,600 72 CMEC 50 167 13,600Control 9 None — <1 <88

Example 74

Example 74 demonstrates the utility of the amorphous dispersion of thepresent invention with an additional CETP inhibitor. The following drugwas incorporated into an amorphous solid dispersion:[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester (“Drug 12”). This compound has a solubility inwater of less than 1 μg/mL, with a Clog P value of 7.8. A spray-driedsolid amorphous dispersion of Drug 12 and HPMCAS-MF was preparedfollowing the procedures outlined in Examples 43 through 46. Table 32summarizes the preparation parameters. Example 74 comprised 25 wt % Drug12.

TABLE 32 Drug Concentration- Polymer Solvent Drug Mass enhancing MassMass Spray Ex. No. (g) Polymer (g) Solvent (g) Apparatus 74 12 0.020HPMCAS-MF 0.060 acetone 25.0 mini

Control 14

The comparative composition of Control 14 consisted of 1.8 mg of thecrystalline form of Drug 12 alone.

Example 75

The spray-dried dispersion of Example 74 was evaluated in an in vitrodissolution test using the procedures described in Example 8. The amountof the dispersion added to the microcentrifuge tube was 7.2 mg,resulting in 1000 μg/ml Drug 12 in solution if all of the drug haddissolved. The results of this test are presented in Table 33.

For Control 14, an in vitro dissolution test was performed using theprocedure described in Example 8, except that 1.8 mg of crystalline drugwas placed in a microcentrifuge tube and mixed with 1.8 mL of PBS. Thetest results are included in Table 33.

TABLE 33 Drug 12 Time Concentration AUC Example (min) (μg/mL)(min-μg/mL) 74 0 0 0 4 479 1,000 10 448 3,700 30 434 8,100 60 399 16,50090 361 35,500 1200 157 323,000 C14 0 0 0 4 <1 <2 10 <1 <8 20 <1 <18 40<1 <38 90 <1 <88 1200 <1 <1,200

The results are summarized in Table 34. The composition of Example 74provided greater concentration-enhancement than that of the crystallinedrug alone (Control 14), providing a C_(max,90) value that was at least479-fold that of the crystalline drug alone, and an AUC₉₀ value that wasat least 403-fold that of the crystalline drug alone.

TABLE 34 Concentration Concentration- of Drug in the AUC₉₀ enhancingDispersion C_(max, 90) (min- Example Polymer (wt %) (μg/mL) μg/mL) 74HPMCAS-MF 25 479 35,500 Control 14 None — <1 <88

Examples 76 and 77

Spray-dried solid amorphous dispersions of Drug 2 and carboxymethylethyl cellulose from Freund Industrial Co. of Tokyo, Japan, wereprepared following the procedures outlined in Examples 43 through 46.Table 35 summarizes the preparation parameters. Example 76 comprised 25wt % Drug 2, while Example 77 comprised 40 wt % Drug 2.

TABLE 35 Drug Concentration- Polymer Solvent Drug Mass enhancing MassMass Spray Ex. No. (g) Polymer* (g) Solvent (g) Apparatus 76 2 0.2007CMEC 0.5995 1:1 Ethanol: 30.0 mini ethylacetate 77 2 0.2992 CMEC 0.44931:1 Ethanol: 30.0 mini ethylacetate *Polymer designation: CMEC =carboxymethyl ethyl cellulose

Example 78

The spray-dried dispersions of Examples 76 and 77 were evaluated in anin vitro dissolution test using the procedures described in Example 8.The amount of each dispersion added to the microcentrifuge tube wasadjusted such that the concentration of Drug 2 in solution if all of thedrug had dissolved was 1000 μg/ml. The results of these tests arepresented in Table 36.

TABLE 36 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)76 0 0 0 4 783 1,600 10 922 6,700 30 898 15,800 60 889 33,700 90 82876,600 1200 339 724,300 77 0 0 0 4 192 400 10 401 2,200 20 501 6,700 40535 17,000 90 464 42,000 1200 188 403,900

The results are summarized in Table 37, which also includes the data forControl 2 (Drug 2 alone), which was tested under the same conditions.The results show that the dissolution results for the compositions ofExamples 76 and 77 were much better than that of the crystalline drugalone (Control 2), providing C_(max,90) values that were at least922-fold and 535-fold that of the crystalline drug alone, and AUC₉₀values that were at least 870-fold and 477-fold that of the crystallinedrug alone, respectively.

TABLE 37 Concentration of Drug Concentration- in the enhancingDispersion C_(max, 90) AUC₉₀ Example Polymer (wt %) (μg/mL) (min-μg/mL)76 CMEC 25 922 76,600 77 CMEC 40 535 42,000 Control 2 None — <1 <88

Example 79

The following process was used to form a spray-dried dispersioncontaining 25 wt % Drug 2 and 75 wt % HPMCAS-HG. First, a 10,000 g spraysolution was formed containing 2.5 wt % Drug 2, 7.5 wt % HPMCAS-MG, and90% acetone as follows. The HPMCAS-HG and acetone were combined in acontainer and mixed for at least 2 hours, allowing the HPMCAS todissolve. The resulting mixture had a slight haze after the entireamount of polymer had been added. Next, Drug 2 was added directly tothis mixture, and the mixture stirred for an additional 2 hours. Thismixture was then filtered by passing it through a filter with a screensize of 250 μm to remove any large insoluble material from the mixture,thus forming the spray solution.

The spray-dried dispersion was then formed using the followingprocedure. The spray solution was pumped using a high-pressure pump (aZenith Z-Drive 2000 High-Pressure Gear Pump), to a spray drier (a Nirotype XP Portable Spray-Dryer with a Liquid-Feed Process Vessel)(“PSD-1”), equipped with a pressure nozzle (Spraying Systems PressureNozzle and Body) (SK 71-16). The PSD-1 was equipped with a 9-inchchamber extension. The 9-inch chamber extension was added to the spraydryer to increase the vertical length of the dryer. The added lengthincreased the residence time within the dryer, which allowed the productto dry before reaching the angled section of the spray dryer. The spraydrier was also equipped with a gas-dispersing means for introduction ofthe drying gas to the spray drying chamber. The gas-dispersing meansconsisted of a plate coextensive with the interior of the drying chamber(about 0.8 m diameter) and bearing a multiplicity of 1.7 mm perforationsoccupying about 1% of the surface area of the plate. The perforationswere uniformly distributed across the plate, except that the density ofperforations at the center 0.2 m of the diffuser plate was about 25% ofthe density of perforations in the outer part of the gas dispersingmeans. The use of the diffuser plate resulted in organized plug flow ofdrying gas through the drying chamber and dramatically decreased productrecirculation within the spray dryer. The nozzle sat flush with thediffuser plate during operation. The spray solution was pumped to thespray drier at about 195 gm/min at a pressure of about 100 psig. Dryinggas (e.g., nitrogen) was circulated through the diffuser plate at aninlet temperature of about 106° C. The evaporated solvent and wet dryinggas exited the spray drier at a temperature of 45±4° C. The spray-drieddispersion formed by this process was collected in a cyclone, and hadhave a bulk specific volume of about 5 cm³/gm, with a mean particle sizeof about 80 μm.

The dispersion formed using the above procedure was post-dried using aGruenberg single-pass convection tray dryer operating at 40° C. for 25hours. Following drying, the dispersion was equilibrated with ambientair and humidity (e.g., 20° C./50% RH).

Typical properties of the dispersion after secondary drying were asfollows:

TABLE 38 Bulk Properties Tray Dried (After Secondary Drying) @ 40° C.Bulk Specific Volume (cc/g) 5.0 Tapped Specific Volume (cc/g) 3.2Hausner Ratio 1.56 Mean Particle Diameter (μm) 80 D₁₀, D₅₀, D₉₀ * (μm)25, 73, 143 Span (D₉₀ − D₁₀)/D₅₀ 1.60 Residual Acetone 3.0% (BeforeSecondary Drying) * 10 vol % of the particles had a diameter that wassmaller than D₁₀; 50 vol % of the particles had a diameter that wassmaller than D₅₀, and 90 vol % of the particles had a diameter that wassmaller than D₉₀.

Example 80

A solid amorphous dispersion comprising 25 wt % Drug 2 in thepolyoxyethylene-polyoxypropylene copolymer PLURONIC F127 was preparedvia a melt-congeal process following the procedures outlined in Example58, with the exceptions noted in Table 39.

TABLE 39 Concentration of Drug in Drug Concentration- Polymer PolymerMass enhancing Mass Example (wt %) (gm) Polymer (gm) 80 25 1.9997Pluronic F-127 6.0012This dispersion was evaluated in an in vitro dissolution test using theprocedures outlined in Example 65. The results of these tests arepresented in Table 40.

TABLE 40 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)80 0 0 0 4 729 1,500 10 789 6,000 20 721 13,600 40 692 27,700 90 54458,600 1200 124 429,500

The results are summarized in Table 41, which also includes the data forControl 2, which was tested under the same conditions. The results showthat the dissolution results for the composition of Example 80 was muchbetter than that of the crystalline drug alone (Control 2), providing aC_(max,90) value that was greater than 789-fold that of the crystallinedrug alone, and an AUC₉₀ value that was greater than 665-fold that ofthe crystalline drug alone.

TABLE 41 Concentration- Concentration enhancing Of Drug in C_(max, 90)AUC₉₀ Example Polymer Polymer (μg/mL) (min-μg/mL) 80 Pluronic F-127 25789 58,600 Control 2 None — <1 <88

Examples 81-82

Solid amorphous dispersions comprising 25 wt % Drug 2 andcarboxymethylethyl cellulose (CMEC) (Example 81) and 35 wt % Drug 2 andCMEC (Example 82) were prepared via a spray drying process following theprocedures outlined in Example 79, with the exceptions noted in Table42. The solid amorphous dispersions were dried overnight in a tray drierat 40° C.

TABLE 42 Drug 2 Concentration- Polymer Solvent Spray Atomization InletOutlet Mass enhancing Mass Mass Rate Presssure Temp. Temp. Ex. (gm)Polymer (gm) Solvent (gm) (gm/min) (psig) (° C.) (° C.) 81 2.5 CMEC 7.5Acetone 90 190 200 110 40 82 4.2 CMEC 7.8 Acetone 138 200 100 110 45The dispersions were evaluated in an in vitro dissolution test using theprocedures outlined in Example 8. The results of these tests arepresented in Table 43.

TABLE 43 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min-μg/mL)81 0 0 0 4 537 1,100 10 772 5,000 20 814 12,900 40 818 29,300 90 81470,000 1200 408 748,100 82 0 0 0 4 321 600 10 567 3,300 20 642 9,300 40637 22,100 90 629 53,800 1200 247 541,100

The results are summarized in Table 44, which also includes the data forControl 2, which was tested under the same conditions. The results showthat the dissolution results for the compositions of Examples 81 and 82were much better than that of the crystalline drug alone (Control 2),providing C_(max,90) values that were greater than 818-fold and 642-foldthat of the crystalline drug alone, and AUC₉₀ values that were greaterthan 795-fold and 611-fold that of the crystalline drug alone,respectively.

TABLE 44 Concentration Concentration- of Drug enhancing in PolymerC_(max, 90) AUC₉₀ Example Polymer (wt %) (μg/mL) (min-μg/mL) 81 CMEC 25818 70,000 82 CMEC 35 642 53,800 Control 2 None — <1 <88

Example 83

The compositions of Examples 80, 81, and 82 were used as oral powdersfor constitution (OPC) for evaluating the performance of thecompositions in in vivo tests using male beagle dogs. The OPC was dosedas a suspension in a solution containing 0.5 wt % hydroxypropylcellulose METHOCEL® (from Dow Chemical Co.), and was prepared asfollows. First, 7.5 g of METHOCEL® was weighed out and added slowly toapproximately 490 ml of water at 90-100° C. to form a METHOCEL®suspension. After all the METHOCEL® was added, 1000 mL of cool/roomtemperature water was added to the suspension, which was then placed inan ice water bath. When all of the METHOCEL® had dissolved, 2.55 g ofpolyoxyethylene 20 sorbitan monooleate (TWEEN 80) were added and themixture stirred until the TWEEN 80 had dissolved, thus forming a stocksuspension solution.

To form the OPC, sufficient quantity of the test composition to resultin a 90 mgA amount of Drug 2 was accurately weighed and placed into amortar. (“mgA” refers to mg of active drug.) A 20 mL quantity of thestock suspension solution was added to the mortar and the testcomposition was mixed with a pestle. Additional METHOCEL® suspension wasadded gradually with mixing until a total of 400 mL of the stocksuspension solution had been added to the mortar. The suspension wasthen transferred to a flask, thus forming the OPC. This process wasrepeated for each of the compositions of Examples 74, 75, and 76. Inaddition, an OPC containing 90 mgA of amorphous Drug 2 (Control 15) wasprepared using the same procedure.

Six male beagle dogs were each dosed with the OPC. On the day of thestudy, the dogs in a fasted state were dosed with the OPC using a gavagetube and a syringe. Whole blood samples were taken from the jugular veinand analyzed for the concentration of Drug 2 using the proceduresoutlined in Examples 18-20. The results of these tests are presented inTable 45 and show that the compositions of the present inventionprovided enhanced drug concentration and relative bioavailabilityrelative to the amorphous Drug 2 control (Control 15).

TABLE 45 C_(max) AUC₍₀₋₂₄₎ Composition (μg/ml) (μg/ml*hr) Example 80 (25wt % Drug 2 in 544 2.1 Pluronic F127) Example 81 (25 wt % Drug 2 inCMEC) 691 1.7 Example 82 (35 wt % Drug 2 in CMEC) 375 1.2 Control 15(amorphous Drug 2) <0.1 <0.2

The composition of Example 80 provided a C_(max) that was more than5440-fold that of the amorphous control, and a relative bioavailabilitythat was greater than 10. The composition of Example 81 provided aC_(max) that was more than 6910-fold that of the amorphous control, anda relative bioavailability that was greater than 8. The composition ofExample 82 provided a C_(max) that was more than 3750-fold that of theamorphous control, and a relative bioavailability that was greater than6.

Examples 84-86

Solid amorphous dispersions comprising 25 wt % Drug 2 and HPMCAS-MG wereprepared via a spray drying process using the procedures outlined inExample 79, except that a 5 feet, nine inches (175 cm) extension on thedryer was used and the pressure nozzle was a Spraying Systems modelSK80-16. Other exceptions are noted in Table 46. The spray solutions toform the dispersions contained 16 wt % solids (Example 84), 18 wt %solids (Example 85), and 20 wt % solids (Example 86). After forming thedispersion, the solid amorphous dispersions were dried overnight in atray drier at 40° C.

TABLE 46 Drug 2 Aqueous- Polymer Solvent Spray Atomization Inlet OutletMass Soluble Mass Mass Rate Press. Temp. Temp. Ex. (gm) Polymer (gm)Solvent (gm) (gm/min) (psig) (° C.) (° C.) 84 75 HPMCAS-MG 225 acetone1575 300 675 132 46 85 100 HPMCAS-MG 300 acetone 1822 300 750 145 40 86125 HPMCAS-MG 375 acetone 2000 420 750 142 35The dispersions were evaluated in an in vitro dissolution test using theprocedures outlined in Example 8. The results of these tests arepresented in Table 47.

TABLE 47 Drug 2 Time Concentration AUC Example (min) (μg/ml) (min-μg/ml)84 0 0 0 4 358 700 10 737 4,000 20 730 11,300 40 679 25,400 90 61257,700 1200 231 525,500 85 0 0 0 4 360 700 10 766 4,100 20 789 11,900 40752 27,300 90 723 64,200 1200 293 628,100 86 0 0 0 4 354 700 10 7764,100 20 847 12,200 40 816 28,800 90 766 68,400 1200 342 682,900

The results are summarized in Table 48, which also includes the data forControl 2, which was tested under the same conditions. The results showthat the compositions of Examples 84, 85, and 86 provided C_(max,90)values that were greater than 737-, 789-, and 847-fold that of thecrystalline drug alone (Control 2), and AUC₉₀ values that were greaterthan 656-, 730-, and 777-fold that of the crystalline drug alone,respectively.

TABLE 48 Concentration Concentration- of Drug Enhancing in PolymerC_(max, 90) AUC₉₀ Example Polymer (wt %) (μg/ml) (min-μg/ml) 84HPMCAS-MG 25 737 57,700 85 HPMCAS-MG 25 789 64,200 86 HPMCAS-MG 25 84768,400 Control 2 None — <1 <88

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A method for forming a pharmaceutical composition, comprising thefollowing steps: (a) forming a solution comprising a cholesteryl estertransfer protein inhibitor (CETPI), a concentration-enhancing polymer,and a solvent; (b) rapidly removing said solvent from said solution ofstep (a) to form a solid amorphous dispersion comprising said CETPI andsaid concentration-enhancing polymer; (c) forming particles from saiddispersion of step (b); wherein said CETPI has a Clog P greater than 4,a solubility in aqueous solution in the absence of saidconcentration-enhancing polymer of less than 10 μg/mL at any pH of from1 to 8, and wherein at least 60 wt % of said CETPI is non-crystalline,and wherein said dispersion has a glass transition temperature that isdifferent than (i) the glass transition temperature of the amorphousform of said CETPI alone and (ii) the glass transition temperature ofsaid concentration-enhancing polymer alone.
 2. The method of claim 1,further comprising step (d) of atomizing said solution of step (a) toform droplets.
 3. The method of claim 2 wherein said step (d) isperformed by spraying said solution through a pressure nozzle.
 4. Themethod of claim 1 wherein step (b) is conducted by spray-drying.
 5. Themethod of claim 1 wherein step (b) is conducted by spray-coating.
 6. Themethod of claim 1 wherein said solid amorphous dispersion of step (b) issubstantially homogeneous such that less than 20 wt % of said CETPI ispresent in relatively pure non-crystalline domains in said dispersion.7. The method of claim 6 wherein said solid amorphous dispersioncomprises a solid solution of said CETPI in said concentration-enhancingpolymer.
 8. The method of claim 1 wherein the melting point of saidCETPI is ≦150° C.
 9. The method of claim 1 wherein said CETPI issubstantially amorphous and said dispersion is substantiallyhomogeneous.
 10. The method of claim 1 wherein said composition providesa maximum concentration of said CETPI in a use environment that is atleast 10-fold the equilibrium concentration of said CETPI provided by acontrol composition consisting essentially of an equivalent amount ofsaid CETPI alone.
 11. The method of claim 1 wherein said compositionprovides in a use environment an area under the concentration versustime curve for any period of at least 90 minutes between the time ofintroduction into said use environment and about 270 minutes followingintroduction that is at least about 5-fold that of a control compositionconsisting essentially of an equivalent amount of said CETPI alone. 12.The method of claim 1 wherein said composition provides a relativebioavailability that is at least 4-fold that of a control compositionconsisting essentially of an equivalent amount of said CETPI alone. 13.The method of claim 1 wherein said concentration-enhancing polymer isselected from vinyl polymers and copolymers having substituents ofhydroxyl, alkylacyloxy, or cyclicamido; polyvinyl alcohols that have atleast a portion of their repeat units in the unhydrolyzed (vinylacetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; poloxamers; polyethylene polyvinyl alcohol copolymers,carboxylic acid functionalized polymethacrylates and carboxylic acidfunctionalized polyacrylates; amine-functionalized polyacrylates andpolymethacrylates; proteins; and carboxylic acid functionalizedstarches, hydroxypropyl methyl cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose succinate, hydroxypropyl celluloseacetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, carboxymethylcellulose, carboxymethylethyl cellulose, cellulose acetate phthalate,methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, hydroxypropyl methyl cellulose acetate succinate phthalate,hydroxypropyl methyl cellulose succinate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.
 14. The method of claim 1 wherein saidCETPI is3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol.15. The method of claim 1 wherein said CETPI is propanethioic acid,2-methyl-S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester.